Comprehensive Physiology Wiley Online Library

Contribution of Adipose Tissue to Development of Cancer

Full Article on Wiley Online Library



ABSTRACT

Solid tumor growth and metastasis require the interaction of tumor cells with the surrounding tissue, leading to a view of tumors as tissue‐level phenomena rather than exclusively cell‐intrinsic anomalies. Due to the ubiquitous nature of adipose tissue, many types of solid tumors grow in proximate or direct contact with adipocytes and adipose‐associated stromal and vascular components, such as fibroblasts and other connective tissue cells, stem and progenitor cells, endothelial cells, innate and adaptive immune cells, and extracellular signaling and matrix components. Excess adiposity in obesity both increases risk of cancer development and negatively influences prognosis in several cancer types, in part due to interaction with adipose tissue cell populations. Herein, we review the cellular and noncellular constituents of the adipose “organ,” and discuss the mechanisms by which these varied microenvironmental components contribute to tumor development, with special emphasis on obesity. Due to the prevalence of breast and prostate cancers in the United States, their close anatomical proximity to adipose tissue depots, and their complex epidemiologic associations with obesity, we particularly highlight research addressing the contribution of adipose tissue to the initiation and progression of these cancer types. Obesity dramatically modifies the adipose tissue microenvironment in numerous ways, including induction of fibrosis and angiogenesis, increased stem cell abundance, and expansion of proinflammatory immune cells. As many of these changes also resemble shifts observed within the tumor microenvironment, proximity to adipose tissue may present a hospitable environment to developing tumors, providing a critical link between adiposity and tumorigenesis. © 2018 American Physiological Society. Compr Physiol 8:237‐282, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Tumors as communities. Tumor cells coexist with a variety of stromal and immune cells, and reside in a complex mixture of signaling molecules and extracellular matrix components. Adjacent adipose tissue may provide a hospitable environment to developing tumors.
Figure 2. Figure 2. The adipose organ is comprised of several distinct adipose depots. Adipose depot locations and subtypes in (A) humans and (B) mice [panel B adapted from () with permission].
Figure 3. Figure 3. Approximate composition of human white adipose tissue stromal‐vascular fraction (percent cellularity).
Figure 4. Figure 4. Rising global and US obesity rates. (A) Global age‐adjusted prevalence of obesity in men and women, 1975 and 2014; (B) Class III obesity (BMI >40), globally and US; and (C) US obesity prevalence by race, ethnicity ().
Figure 5. Figure 5. Comparison of mouse and human mammary gland anatomical structure. (A) Murine ductal elongation and branching occur at the Terminal End Buds (TEBs). (B) The human mammary gland is extensively branched, culminating in the functional terminal ductal lobular unit (TDLU).
Figure 6. Figure 6. Comparison of mouse and human mammary gland histology. Left: Adult mouse mammary fat pad from nulliparous C57BL/6 mouse (4× and 10×, H&E staining). Right: H&E‐stained normal human breast tissue. Arrowhead and asterisks in right panel refer to loose intra‐ and dense interlobular stroma, respectively. Human histology images courtesy of Melissa Troester and the UNC Normal Breast Study (unpublished).
Figure 7. Figure 7. Adipose‐breast cancer interactions in mice and humans. (A) Early invasive lesions in H&E‐stained mammary gland tissue from the C3(1)‐TAg genetically engineered mouse model of spontaneous basal‐like breast cancer (unpublished images). (B) Human breast cancer—female, 50 years, lobular carcinoma, grade 1, Elston‐Ellis score 5. Image credit: The Human Protein Atlas ().
Figure 8. Figure 8. Anatomical comparison of mouse (left) and human (right) prostate glands.
Figure 9. Figure 9. Desmoplasia and cancer‐associated adipocytes. (A) Mammary tumors from C3(1)‐TAg mice are stained with Hematoxylin/eosin (left) and Masson's trichrome (right) (unpublished). In tumors, chronic activation of the wound‐repair response results in desmoplasia, or excess collagenous extracellular matrix production, within tumors. Asterisks (*) indicate desmoplastic stroma. (B) Cancer‐associated adipocytes (black arrows) at or near the tumor invasive front become smaller and exhibit decreased expression of adipocyte markers, while the number of fibroblast‐like cells increases.
Figure 10. Figure 10. Obesity‐associated modifications in the adipose tissue microenvironment. Adipose tissue expansion in obesity occurs in association with extracellular matrix changes such as fibrosis. Adipocyte hypertrophy and hypoxia trigger macrophage infiltration and crown‐like structure formation, which further exacerbates development of fibrosis and inflammation.
Figure 11. Figure 11. HGF/cMET: an oncogenic signaling cascade. HGF secretion by stromal cells such as fibroblasts, adipocytes, and macrophages initiates an invasive growth program in epithelial cells.
Figure 12. Figure 12. Adipocyte subtypes and secreted factors. White adipocytes contain a large, unilocular lipid droplet and are specialized for storage of neutral lipids. Brown and/or beige adipocytes have increased mitochondrial content relative to white adipocytes and play important roles in thermogenesis. “Pink” adipocytes have been described in murine mammary gland, arising exclusively during pregnancy and lactation. Collectively, adipocytes secrete a broad range of signaling molecules.
Figure 13. Figure 13. Adipocytes promote tumor progression and metastasis. Adipocytes may provide metabolic substrates directly to cancer cells, or may indirectly influence cancer metabolism through exosome secretion. Adipocytes also secrete a variety of factors that promote tumor growth, EMT (epithelial‐mesenchymal transition), acquisition of stem‐like features, invasive behavior, and metastasis.
Figure 14. Figure 14. Obesity, cancer increase circulating ASCs. Human adipose tissue stroma is a rich source of multipotent ASCs, which enter the circulation and traffic to other tissues. This “shedding” process is increased in obese and/or tumor‐bearing individuals. Tumor chemokine secretion (e.g., CXCL1, CXCL8) is influenced by obesity and is implicated in ASC recruitment to developing tumors and differentiation into stromal populations such as fibroblasts, pericytes, and adipocytes.
Figure 15. Figure 15. Hypoxia & the angiogenic switch. An extensive list of proangiogenic factors is involved in both induction of the angiogenic switch in developing solid tumors and expansion of adipose tissue during progression to obesity. As tumor cells proliferate or adipocytes hypertrophy, hypoxia develops and triggers stabilization of the HIF‐1 complex, a transcription factor which promotes increased production of growth factors such as VEGF‐A, FGF1, TGF‐β, HGF, and angiopoietins 1 and 2. Additional proangiogenic factors include the adipokines leptin and adiponectin; cytokines such as TNFα, IL‐6, and IL‐8; and matrix metalloproteases, which degrade the extracellular matrix. Ultimately, increased vascularization alleviates regional hypoxia and facilitates further tissue expansion.
Figure 16. Figure 16. Mammary HGF/cMET signaling in the in C3(1)‐Tag mouse model of basal‐like breast cancer. Obesity increased HGF production by stromal cells, promoting tumor growth and angiogenesis. HGF/cMET‐mediated tumor promotion was reversible by weight loss or cMET inhibition.
Figure 17. Figure 17. Summary of changes in immune cell profile during progression to obesity. In the lean state, adipose tissue contains a variety of immunoregulatory cells such as M2‐like tissue‐resident macrophages, regulatory T cells, and eosinophils. Within days of exposure to an obesogenic diet neutrophils infiltrate adipose. Over weeks to months, an increase in CD8+ T cells, macrophages, and myeloid‐derived suppressor cells (MDSCs) results in a mix of pro‐ and anti‐inflammatory cells. In prolonged obesity, adipose mast cell content may also increase.
Figure 18. Figure 18. Macrophage activation as a spectrum. Unstimulated macrophages can be polarized in vitro to generate M1 (right) or M2 macrophages (left) using single cytokines or cytokine and other stimuli cocktails. However, tissue macrophages are exquisitely plastic, often expressing one or more markers of both M1 and M2 subtypes. Thus, tissue macrophage activation lies along a spectrum, resulting in mixed phenotype with specific expression and function varying by tissue type and timing of residence.
Figure 19. Figure 19. Adipose tissue macrophage ontogeny. Lineage tracing studies have revealed multiple embryonic sources for tissue‐resident macrophages (e.g., Kupffer cells, microglia) including the yolk sac and fetal liver. However, the contribution of bone marrow monocyte‐derived macrophages to tissue‐resident populations remains ambiguous. Moreover, the relative contribution of yolk sac, fetal liver, and bone marrow‐derived macrophages within adipose tissue depots has not been established, although the overall proportion of inflammatory, bone‐marrow derived macrophages increases in obese adipose.
Figure 20. Figure 20. Tumor‐Associated Neutrophils have N1 and N2‐like phenotypes. (A) Neutrophil content and phenotype is both pro‐ and anti‐tumoral with cytokines such as IFNβ, IL‐1β, TNF‐α activating the N1 or proinflammatory phenotype and TGF‐B driving the N2 immunomodulatory phenotype. The N1 neutrophil releases reactive oxygen species (ROS) and proteins that increase cell recruitment and extravasation [ICAM and CCL3 (MIP‐1‐alpha)]. N1 neutrophils support cytotoxic CD8+ T cell activity. N2 neutrophils have a less segmented nucleus than typical and secretes many angiogenic and immunosuppressive mediators, expressing arginase 1 for example. ROS secreted by both N1 and N2 may both promote genotoxicity in tumor initiation, or in contrast, can be cytotoxic to growing tumors. The timing and phenotype of neutrophil influx in obesity and tumor progression warrants further study. (B) Neutrophils infiltrate adipose early during progression to obesity. Neutrophil production of ROS, for example, through myeloperoxidase (MPO) expression, contributes to oxidative stress and fibrotic changes.
Figure 21. Figure 21. Mast cells: Unappreciated players in adipose and tumor biology. (A) Mast cell content in adipose tissue increases with obesity, with mast cells localized to blood vessels and/or within fibrotic bundles. Obesity is also associated with increased mast cell degranulation, an indicator of a mast cell activation. (B) In cancer, mast cells contribute to tumor progression through release of proangiogenic factors (MMP9, VEGF), immunosuppressive mediators (histamine), or growth factors such as PDGF. Mast cells also secrete cytokines that may promote (arrow) or inhibit (line) tumor progression. Mast cell influence on tumor progression appears to be dependent upon mast cell localization as peri‐ versus intratumoral.


Figure 1. Tumors as communities. Tumor cells coexist with a variety of stromal and immune cells, and reside in a complex mixture of signaling molecules and extracellular matrix components. Adjacent adipose tissue may provide a hospitable environment to developing tumors.


Figure 2. The adipose organ is comprised of several distinct adipose depots. Adipose depot locations and subtypes in (A) humans and (B) mice [panel B adapted from () with permission].


Figure 3. Approximate composition of human white adipose tissue stromal‐vascular fraction (percent cellularity).


Figure 4. Rising global and US obesity rates. (A) Global age‐adjusted prevalence of obesity in men and women, 1975 and 2014; (B) Class III obesity (BMI >40), globally and US; and (C) US obesity prevalence by race, ethnicity ().


Figure 5. Comparison of mouse and human mammary gland anatomical structure. (A) Murine ductal elongation and branching occur at the Terminal End Buds (TEBs). (B) The human mammary gland is extensively branched, culminating in the functional terminal ductal lobular unit (TDLU).


Figure 6. Comparison of mouse and human mammary gland histology. Left: Adult mouse mammary fat pad from nulliparous C57BL/6 mouse (4× and 10×, H&E staining). Right: H&E‐stained normal human breast tissue. Arrowhead and asterisks in right panel refer to loose intra‐ and dense interlobular stroma, respectively. Human histology images courtesy of Melissa Troester and the UNC Normal Breast Study (unpublished).


Figure 7. Adipose‐breast cancer interactions in mice and humans. (A) Early invasive lesions in H&E‐stained mammary gland tissue from the C3(1)‐TAg genetically engineered mouse model of spontaneous basal‐like breast cancer (unpublished images). (B) Human breast cancer—female, 50 years, lobular carcinoma, grade 1, Elston‐Ellis score 5. Image credit: The Human Protein Atlas ().


Figure 8. Anatomical comparison of mouse (left) and human (right) prostate glands.


Figure 9. Desmoplasia and cancer‐associated adipocytes. (A) Mammary tumors from C3(1)‐TAg mice are stained with Hematoxylin/eosin (left) and Masson's trichrome (right) (unpublished). In tumors, chronic activation of the wound‐repair response results in desmoplasia, or excess collagenous extracellular matrix production, within tumors. Asterisks (*) indicate desmoplastic stroma. (B) Cancer‐associated adipocytes (black arrows) at or near the tumor invasive front become smaller and exhibit decreased expression of adipocyte markers, while the number of fibroblast‐like cells increases.


Figure 10. Obesity‐associated modifications in the adipose tissue microenvironment. Adipose tissue expansion in obesity occurs in association with extracellular matrix changes such as fibrosis. Adipocyte hypertrophy and hypoxia trigger macrophage infiltration and crown‐like structure formation, which further exacerbates development of fibrosis and inflammation.


Figure 11. HGF/cMET: an oncogenic signaling cascade. HGF secretion by stromal cells such as fibroblasts, adipocytes, and macrophages initiates an invasive growth program in epithelial cells.


Figure 12. Adipocyte subtypes and secreted factors. White adipocytes contain a large, unilocular lipid droplet and are specialized for storage of neutral lipids. Brown and/or beige adipocytes have increased mitochondrial content relative to white adipocytes and play important roles in thermogenesis. “Pink” adipocytes have been described in murine mammary gland, arising exclusively during pregnancy and lactation. Collectively, adipocytes secrete a broad range of signaling molecules.


Figure 13. Adipocytes promote tumor progression and metastasis. Adipocytes may provide metabolic substrates directly to cancer cells, or may indirectly influence cancer metabolism through exosome secretion. Adipocytes also secrete a variety of factors that promote tumor growth, EMT (epithelial‐mesenchymal transition), acquisition of stem‐like features, invasive behavior, and metastasis.


Figure 14. Obesity, cancer increase circulating ASCs. Human adipose tissue stroma is a rich source of multipotent ASCs, which enter the circulation and traffic to other tissues. This “shedding” process is increased in obese and/or tumor‐bearing individuals. Tumor chemokine secretion (e.g., CXCL1, CXCL8) is influenced by obesity and is implicated in ASC recruitment to developing tumors and differentiation into stromal populations such as fibroblasts, pericytes, and adipocytes.


Figure 15. Hypoxia & the angiogenic switch. An extensive list of proangiogenic factors is involved in both induction of the angiogenic switch in developing solid tumors and expansion of adipose tissue during progression to obesity. As tumor cells proliferate or adipocytes hypertrophy, hypoxia develops and triggers stabilization of the HIF‐1 complex, a transcription factor which promotes increased production of growth factors such as VEGF‐A, FGF1, TGF‐β, HGF, and angiopoietins 1 and 2. Additional proangiogenic factors include the adipokines leptin and adiponectin; cytokines such as TNFα, IL‐6, and IL‐8; and matrix metalloproteases, which degrade the extracellular matrix. Ultimately, increased vascularization alleviates regional hypoxia and facilitates further tissue expansion.


Figure 16. Mammary HGF/cMET signaling in the in C3(1)‐Tag mouse model of basal‐like breast cancer. Obesity increased HGF production by stromal cells, promoting tumor growth and angiogenesis. HGF/cMET‐mediated tumor promotion was reversible by weight loss or cMET inhibition.


Figure 17. Summary of changes in immune cell profile during progression to obesity. In the lean state, adipose tissue contains a variety of immunoregulatory cells such as M2‐like tissue‐resident macrophages, regulatory T cells, and eosinophils. Within days of exposure to an obesogenic diet neutrophils infiltrate adipose. Over weeks to months, an increase in CD8+ T cells, macrophages, and myeloid‐derived suppressor cells (MDSCs) results in a mix of pro‐ and anti‐inflammatory cells. In prolonged obesity, adipose mast cell content may also increase.


Figure 18. Macrophage activation as a spectrum. Unstimulated macrophages can be polarized in vitro to generate M1 (right) or M2 macrophages (left) using single cytokines or cytokine and other stimuli cocktails. However, tissue macrophages are exquisitely plastic, often expressing one or more markers of both M1 and M2 subtypes. Thus, tissue macrophage activation lies along a spectrum, resulting in mixed phenotype with specific expression and function varying by tissue type and timing of residence.


Figure 19. Adipose tissue macrophage ontogeny. Lineage tracing studies have revealed multiple embryonic sources for tissue‐resident macrophages (e.g., Kupffer cells, microglia) including the yolk sac and fetal liver. However, the contribution of bone marrow monocyte‐derived macrophages to tissue‐resident populations remains ambiguous. Moreover, the relative contribution of yolk sac, fetal liver, and bone marrow‐derived macrophages within adipose tissue depots has not been established, although the overall proportion of inflammatory, bone‐marrow derived macrophages increases in obese adipose.


Figure 20. Tumor‐Associated Neutrophils have N1 and N2‐like phenotypes. (A) Neutrophil content and phenotype is both pro‐ and anti‐tumoral with cytokines such as IFNβ, IL‐1β, TNF‐α activating the N1 or proinflammatory phenotype and TGF‐B driving the N2 immunomodulatory phenotype. The N1 neutrophil releases reactive oxygen species (ROS) and proteins that increase cell recruitment and extravasation [ICAM and CCL3 (MIP‐1‐alpha)]. N1 neutrophils support cytotoxic CD8+ T cell activity. N2 neutrophils have a less segmented nucleus than typical and secretes many angiogenic and immunosuppressive mediators, expressing arginase 1 for example. ROS secreted by both N1 and N2 may both promote genotoxicity in tumor initiation, or in contrast, can be cytotoxic to growing tumors. The timing and phenotype of neutrophil influx in obesity and tumor progression warrants further study. (B) Neutrophils infiltrate adipose early during progression to obesity. Neutrophil production of ROS, for example, through myeloperoxidase (MPO) expression, contributes to oxidative stress and fibrotic changes.


Figure 21. Mast cells: Unappreciated players in adipose and tumor biology. (A) Mast cell content in adipose tissue increases with obesity, with mast cells localized to blood vessels and/or within fibrotic bundles. Obesity is also associated with increased mast cell degranulation, an indicator of a mast cell activation. (B) In cancer, mast cells contribute to tumor progression through release of proangiogenic factors (MMP9, VEGF), immunosuppressive mediators (histamine), or growth factors such as PDGF. Mast cells also secrete cytokines that may promote (arrow) or inhibit (line) tumor progression. Mast cell influence on tumor progression appears to be dependent upon mast cell localization as peri‐ versus intratumoral.
References
 1.The Human Protein Atlas, www.proteinatlas.org. Human breast cancer ‐ Female, 50 years, lobular carcinoma, grade 1, Elston‐Ellis score 5. Image data available at the following URL: v16.proteinatlas.org/learn/dictionary/cancer/breast+cancer+4.
 2.Abrahamson PE, Gammon MD, Lund MJ, Flagg EW, Porter PL, Stevens J, Swanson CA, Brinton LA, Eley JW, Coates RJ. General and abdominal obesity and survival among young women with breast cancer. Cancer Epidemiol Biomarkers Prev 15: 1871‐1877, 2006.
 3.Aggarwal BB, Gehlot P. Inflammation and cancer: How friendly is the relationship for cancer patients? Curr Opin Pharmacol 9: 351‐369, 2009.
 4.Agustsson T, Ryden M, Hoffstedt J, van Harmelen V, Dicker A, Laurencikiene J, Isaksson B, Permert J, Arner P. Mechanism of increased lipolysis in cancer cachexia. Cancer Res 67: 5531‐5537, 2007.
 5.Akuthota P, Wang HB, Spencer LA, Weller PF. Immunoregulatory roles of eosinophils: A new look at a familiar cell. Clin Exp Allergy 38: 1254‐1263, 2008.
 6.Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7: 139‐147, 2007.
 7.Albrecht I, Christofori G. Molecular mechanisms of lymphangiogenesis in development and cancer. Int J Dev Biol 55: 483‐494, 2011.
 8.Allen E, Mieville P, Warren CM, Saghafinia S, Li L, Peng MW, Hanahan D. Metabolic symbiosis enables adaptive resistance to anti‐angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15: 1144‐1160, 2016.
 9.Altintas MM, Azad A, Nayer B, Contreras G, Zaias J, Faul C, Reiser J, Nayer A. Mast cells, macrophages, and crown‐like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res 52: 480‐488, 2011.
 10.Altintas MM, Rossetti MA, Nayer B, Puig A, Zagallo P, Ortega LM, Johnson KB, McNamara G, Reiser J, Mendez AJ, Nayer A. Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long‐standing diet‐induced obese mice. Lipids Health Dis 10: 198, 2011.
 11.Alves MJ, Figuerêdo RG, Azevedo FF, Cavallaro DA, Neto NIP, Lima JDC, Matos‐Neto E, Radloff K, Riccardi DM, Camargo RG, De Alcântara PSM, Otoch JP, Junior MLB, Seelaender M. Adipose tissue fibrosis in human cancer cachexia: The role of TGFβ pathway. BMC Cancer 17: 190, 2017.
 12.Amadou A, Ferrari P, Muwonge R, Moskal A, Biessy C, Romieu I, Hainaut P. Overweight, obesity and risk of premenopausal breast cancer according to ethnicity: A systematic review and dose‐response meta‐analysis. Obes Rev 14: 665‐678, 2013.
 13.Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M. Local proliferation of macrophages contributes to obesity‐associated adipose tissue inflammation. Cell Metab 19: 162‐171, 2014.
 14.Amarnath S, Mangus CW, Wang JCM, Wei F, He A, Kapoor V, Foley JE, Massey PR, Felizardo TC, Riley JL, Levine BL, June CH, Medin JA, Fowler DH. The PDL1‐PD1 axis converts human Th1 cells into regulatory T cells. Sci Transl Med 3: 111ra120, 2011.
 15.Amor S, Iglesias‐de la Cruz MC, Ferrero E, Garcia‐Villar O, Barrios V, Fernandez N, Monge L, Garcia‐Villalon AL, Granado M. Peritumoral adipose tissue as a source of inflammatory and angiogenic factors in colorectal cancer. Int J Colorectal Dis 31: 365‐375, 2016.
 16.Anderson GL, Neuhouser ML. Obesity and the risk for premenopausal and postmenopausal breast cancer. Cancer Prev Res (Phila) 5: 515‐521, 2012.
 17.Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y, Song X, Dvozkin T, Krelin Y, Voronov E. The involvement of IL‐1 in tumorigenesis, tumor invasiveness, metastasis and tumor‐host interactions. Cancer Metastasis Rev 25: 387‐408, 2006.
 18.Arendt LM, McCready J, Keller PJ, Baker DD, Naber SP, Seewaldt V, Kuperwasser C. Obesity promotes breast cancer by CCL2‐mediated macrophage recruitment and angiogenesis. Cancer Res 73: 6080‐6093, 2013.
 19.Arngrim N, Simonsen L, Holst JJ, Bulow J. Reduced adipose tissue lymphatic drainage of macromolecules in obese subjects: A possible link between obesity and local tissue inflammation [quest]. Int J Obes 37: 748‐750, 2013.
 20.Atherton AJ, O'Hare MJ, Buluwela L, Titley J, Monaghan P, Paterson HF, Warburton MJ, Gusterson BA. Ectoenzyme regulation by phenotypically distinct fibroblast sub‐populations isolated from the human mammary gland. J Cell Sci 107(Pt 10): 2931‐2939, 1994.
 21.Atherton AJ, Warburton MJ, O'Hare MJ, Monaghan P, Schuppan D, Gusterson BA. Differential expression of type XIV collagen/undulin by human mammary gland intralobular and interlobular fibroblasts. Cell Tissue Res 291: 507‐511, 1998.
 22.Augustin H. Obesity and prostate cancer: An ambiguous relationship. Eur J Cancer 43: 1114‐1116, 2007.
 23.Ayala G, Tuxhorn JA, Wheeler TM, Frolov A, Scardino PT, Ohori M, Wheeler M, Spitler J, Rowley DR. Reactive stroma as a predictor of biochemical‐free recurrence in prostate cancer. Clin Cancer Res 9: 4792‐4801, 2003.
 24.Azrad M, Demark‐Wahnefried W. The association between adiposity and breast cancer recurrence and survival: A review of the recent literature. Curr Nutr Rep 3: 9‐15, 2014.
 25.Azzi S, Hebda JK, Gavard J. Vascular permeability and drug delivery in cancers. Front Oncol 3: 211, 2013.
 26.Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 4: 540‐550, 2004.
 27.Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer 9: 361‐371, 2009.
 28.Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet 357: 539‐545, 2001.
 29.Baratelli F, Lee JM, Hazra S, Lin Y, Walser TC, Schaue D, Pak PS, Elashoff D, Reckamp K, Zhang L, Fishbein MC, Sharma S, Dubinett SM. PGE(2) contributes to TGF‐β induced T regulatory cell function in human non‐small cell lung cancer. Am J Transl Res 2: 356‐367, 2010.
 30.Baratelli F, Lin Y, Zhu L, Yang SC, Heuze‐Vourc'h N, Zeng G, Reckamp K, Dohadwala M, Sharma S, Dubinett SM. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175: 1483‐1490, 2005.
 31.Barlow J, Hirschberg Jensen V, Jastroch M, Affourtit C. Palmitate‐induced impairment of glucose‐stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets. Biochem J 473: 487‐496, 2015.
 32.Barrington WE, Schenk JM, Etzioni R, Arnold KB, Neuhouser ML, Thompson IM, Jr., Lucia MS, Kristal AR. Difference in association of obesity with prostate cancer risk between US African American and non‐Hispanic white men in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA Oncol 1: 342‐349, 2015.
 33.Basen‐Engquist K, Chang M. Obesity and cancer risk: Recent review and evidence. Curr Oncol Rep 13: 71‐76, 2011.
 34.Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH. Quantification of regulatory T cells enables the identification of high‐risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24: 5373‐5380, 2006.
 35.Batista ML, Jr., Henriques FS, Neves RX, Olivan MR, Matos‐Neto EM, Alcantara PS, Maximiano LF, Otoch JP, Alves MJ, Seelaender M. Cachexia‐associated adipose tissue morphological rearrangement in gastrointestinal cancer patients. J Cachexia Sarcopenia Muscle 7: 37‐47, 2016.
 36.Baylor Breast Care Center BCoM. CRIZENT: Crizotinib and Sunitinib in Metastatic Breast Cancer. In: ClinicalTrials.gov identifier, NCT02074878, 2015.
 37.Beckham TH, Lu P, Cheng JC, Zhao D, Turner LS, Zhang X, Hoffman S, Armeson KE, Liu A, Marrison T, Hannun YA, Liu X. Acid ceramidase‐mediated production of sphingosine 1‐phosphate promotes prostate cancer invasion through upregulation of cathepsin B. Int J Cancer 131: 2034‐2043, 2012.
 38.Bekes EM, Schweighofer B, Kupriyanova TA, Zajac E, Ardi VC, Quigley JP, Deryugina EI. Tumor‐recruited neutrophils and neutrophil TIMP‐free MMP‐9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol 179: 1455‐1470, 2011.
 39.Bell LN, Ward JL, Degawa‐Yamauchi M, Bovenkerk JE, Jones R, Cacucci BM, Gupta CE, Sheridan C, Sheridan K, Shankar SS, Steinberg HO, March KL, Considine RV. Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity. Am J Physiol Endocrinol Metab 291: E843‐E848, 2006.
 40.Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3: 401‐410, 2003.
 41.Bergman RN, Stefanovski D, Buchanan TA, Sumner AE, Reynolds JC, Sebring NG, Xiang AH, Watanabe RM. A better index of body adiposity. Obesity (Silver Spring) 19: 1083‐1089, 2011.
 42.Biglia N, Peano E, Sgandurra P, Moggio G, Pecchio S, Maggiorotto F, Sismondi P. Body mass index (BMI) and breast cancer: Impact on tumor histopathologic features, cancer subtypes and recurrence rate in pre and postmenopausal women. Gynecol Endocrinol 29: 263‐267, 2013.
 43.Bissell MJ, Kenny PA, Radisky DC. Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: The role of extracellular matrix and its degrading enzymes. Cold Spring Harb Symp Quant Biol 70: 343‐356, 2005.
 44.Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 1: 46‐54, 2001.
 45.Biswas SK, Lewis CE. NF‐kappaB as a central regulator of macrophage function in tumors. J Leukoc Biol 88: 877‐884, 2010.
 46.Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, Dray C, Guiet R, Maridonneau‐Parini I, Le Gonidec S, Couderc B, Escourrou G, Valet P, Muller C. Adipocyte‐derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res 73: 5657‐5668, 2013.
 47.Bodle JC, Teeter SD, Hluck BH, Hardin JW, Bernacki SH, Loboa EG. Age‐related effects on the potency of human adipose‐derived stem cells: Creation and evaluation of superlots and implications for musculoskeletal tissue engineering applications. Tissue Engineering Part C, Methods 20: 972‐983, 2014.
 48.Boehm K, Sun M, Larcher A, Blanc‐Lapierre A, Schiffmann J, Graefen M, Sosa J, Saad F, Parent ME, Karakiewicz PI. Waist circumference, waist‐hip ratio, body mass index, and prostate cancer risk: Results from the North‐American case‐control study Prostate Cancer & Environment Study. Urol Oncol 33: 494.e491‐497, 2015.
 49.Bostwick DG, Cheng L. Urologic Surgical Pathology. St. Louis, MO: Elsevier Health Sciences, 2008.
 50.Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, Redl H, Rubin JP, Yoshimura K, Gimble JM. Stromal cells from the adipose tissue‐derived stromal vascular fraction and culture expanded adipose tissue‐derived stromal/stem cells: A joint statement of the International Federation for Adipose Therapeutics (IFATS) and Science and the International Society for Cellular Therapy (ISCT). Cytotherapy 15: 641‐648, 2013.
 51.Boyd NF, Martin LJ, Bronskill M, Yaffe MJ, Duric N, Minkin S. Breast tissue composition and susceptibility to breast cancer. J Natl Cancer Inst 102: 1224‐1237, 2010.
 52.Brakenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P, Cao Y. Angiogenesis inhibitor, TNP‐470, prevents diet‐induced and genetic obesity in mice. Circ Res 94: 1579‐1588, 2004.
 53.Briganti A, Karakiewicz PI, Chun FKH, Suardi N, Gallina A, Abdollah F, Freschi M, Doglioni C, Rigatti P, Montorsi F. Obesity does not increase the risk of lymph node metastases in patients with clinically localized prostate cancer undergoing radical prostatectomy and extended pelvic lymph node dissection. Int J Urol 16: 676‐681, 2009.
 54.Caballero B. The global epidemic of obesity: An overview. Epidemiol Rev 29: 1‐5, 2007.
 55.Calle EE, Rodriguez C, Walker‐Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348: 1625‐1638, 2003.
 56.Calle EE, Thun MJ. Obesity and cancer. Oncogene 23: 6365‐6378, 2004.
 57.Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y, Malaka DO. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat 128: 703‐711, 2011.
 58.Cao R, Bjorndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, Cao Y. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood 107: 3531‐3536, 2006.
 59.Cao R, Brakenhielm, E, Wahlestedt, C, Thyberg, J, Cao, Y. Leptin induces vascular permeability and synergistically. Proc Natl Acad Sci U S A 98: 6390‐6395, 2001.
 60.Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 117: 2362‐2368, 2007.
 61.Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hammerling GJ. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol 16: 609‐617, 2015.
 62.Carter JC, Church FC. Mature breast adipocytes promote breast cancer cell motility. Exp Mol Pathol 92: 312‐317, 2012.
 63.Casbas‐Hernandez P, D'Arcy M, Roman‐Perez E, Brauer HA, McNaughton K, Miller SM, Chhetri RK, Oldenburg AL, Fleming JM, Amos KD. Role of HGF in epithelial–stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ. Breast Cancer Res 15: R82, 2013.
 64.Chan DS, Vieira AR, Aune D, Bandera EV, Greenwood DC, McTiernan A, Navarro Rosenblatt D, Thune I, Vieira R, Norat T. Body mass index and survival in women with breast cancer‐systematic literature review and meta‐analysis of 82 follow‐up studies. Ann Oncol 25: 1901‐1914, 2014.
 65.Chandler EM, Saunders MP, Yoon CJ, Gourdon D, Fischbach C. Adipose progenitor cells increase fibronectin matrix strain and unfolding in breast tumors. Phys Biol 8: 015008, 2011.
 66.Chang CH, Pearce EL. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol 17: 364‐368, 2016.
 67.Chen L, Cook LS, Tang MT, Porter PL, Hill DA, Wiggins CL, Li CI. Body mass index and risk of luminal, HER2‐overexpressing, and triple negative breast cancer. Breast Cancer Res Treat 157: 545‐554, 2016.
 68.Chen L, Han X. Anti‐PD‐1/PD‐L1 therapy of human cancer: Past, present, and future. J Clin Invest 125: 3384‐3391, 2015.
 69.Clark R, Krishnan V, Schoof M, Rodriguez I, Theriault B, Chekmareva M, Rinker‐Schaeffer C. Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models. Am J Pathol 183: 576‐591, 2013.
 70.Cleary MP, Grossmann ME. Minireview: Obesity and breast cancer: the estrogen connection. Endocrinology 150: 2537‐2542, 2009.
 71.Couldrey C, Moitra J, Vinson C, Anver M, Nagashima K, Green J. Adipose tissue: A vital in vivo role in mammary gland development but not differentiation. Dev Dyn 223: 459‐468, 2002.
 72.Coussens LM, Werb Z. Inflammation and cancer. Nature 420: 860‐867, 2002.
 73.Cowen S, McLaughlin SL, Hobbs G, Coad J, Martin KH, Olfert IM, Vona‐Davis L. High‐fat, high‐calorie diet enhances mammary carcinogenesis and local inflammation in MMTV‐PyMT mouse model of breast cancer. Cancers 7: 1125‐1142, 2015.
 74.Cozzo AJ, Sundaram S, Zattra O, Qin Y, Freemerman AJ, Essaid L, Darr DB, Montgomery SA, McNaughton KK, Ezzell JA, Galanko JA, Troester MA, Makowski L. cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)‐Tag model of basal‐like breast cancer. Springerplus 5: 348, 2016.
 75.Curat CA, Miranville A, Sengenès C, Diehl M, Tonus C, Busse R, Bouloumié A. From blood monocytes to adipose tissue‐resident macrophages: Induction of diapedesis by human mature adipocytes. Diabetes 53: 1285‐1292, 2004.
 76.Curat CA, Wegner V, Sengenes C, Miranville A, Tonus C, Busse R, Bouloumie A. Macrophages in human visceral adipose tissue: Increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 49: 744‐747, 2006.
 77.da Silva EZ, Jamur MC, Oliver C. Mast cell function: A new vision of an old cell. J Histochem Cytochem 62: 698‐738, 2014.
 78.Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, Gorkiewicz G, Tamilarasan KP, Kumari P, Trauner M, Zimmermann R, Vesely P, Haemmerle G, Zechner R, Hoefler G. Adipose triglyceride lipase contributes to cancer‐associated cachexia. Science 333: 233‐238, 2011.
 79.Datta K, Muders M, Zhang H, Tindall DJ. Mechanism of lymph node metastasis in prostate cancer. Future Oncol 6: 823‐836, 2010.
 80.Davies LC, Rosas M, Jenkins SJ, Liao C, Scurr MJ, Brombacher F, Fraser DJ, Allen JE, Jones SA, Taylor PR. Distinct bone marrow‐derived and tissue resident macrophage‐lineages proliferate at key stages during inflammation. Nat Commun 4: 2013.
 81.Davies LC, Rosas M, Smith PJ, Fraser DJ, Jones SA, Taylor PR. A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. Eur J Immunol 41: 2155‐2164, 2011.
 82.Davies LC, Taylor PR. Tissue‐resident macrophages: Then and now. Immunology 144: 541‐548, 2015.
 83.Davis BP, Rothenberg ME. Eosinophils and cancer. Cancer Immunol Res 2: 1‐8, 2014.
 84.Dawood S, Broglio K, Gonzalez‐Angulo AM, Kau SW, Islam R, Hortobagyi GN, Cristofanilli M. Prognostic value of body mass index in locally advanced breast cancer. Clin Cancer Res 14: 1718‐1725, 2008.
 85.de Jong JM, Larsson O, Cannon B, Nedergaard J. A stringent validation of mouse adipose tissue identity markers. Am J Physiol Endocrinol Metab 308: E1085‐E1105, 2015.
 86.De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23: 277‐286, 2013.
 87.De Wever O, Demetter P, Mareel M, Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123: 2229‐2238, 2008.
 88.DeFilippis RA, Chang H, Dumont N, Rabban JT, Chen YY, Fontenay GV, Berman HK, Gauthier ML, Zhao J, Hu D, Marx JJ, Tjoe JA, Ziv E, Febbraio M, Kerlikowske K, Parvin B, Tlsty TD. CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues. Cancer Discov 2: 826‐839, 2012.
 89.DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1: 54‐67, 2011.
 90.Deng T, Lyon CJ, Bergin S, Caligiuri MA, Hsueh WA. Obesity, inflammation, and cancer. Annu Rev Pathol 11: 421‐449, 2016.
 91.Ding S, Merkulova‐Rainon T, Han ZC, Tobelem G. HGF receptor up‐regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 101: 4816‐4822, 2003.
 92.Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le Gonidec S, Garrido I, Escourrou G, Valet P, Muller C. Cancer‐associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71: 2455‐2465, 2011.
 93.Direkze NC, Hodivala‐Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA. Bone marrow contribution to tumor‐associated myofibroblasts and fibroblasts. Cancer Res 64: 8492‐8495, 2004.
 94.Divoux A, Moutel S, Poitou C, Lacasa D, Veyrie N, Aissat A, Arock M, Guerre‐Millo M, Clement K. Mast cells in human adipose tissue: Link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metab 97: E1677‐E1685, 2012.
 95.Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A, Basdevant A, Guerre‐Millo M, Poitou C, Zucker J‐D, Bedossa P, Clément K. Fibrosis in human adipose tissue: Composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 59: 2817‐2825, 2010.
 96.Dixit VD. Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr Opin Immunol 22: 521‐528, 2010.
 97.Djonov V, Andres A‐C, Ziemiecki A. Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc Res Tech 52: 182‐189, 2001.
 98.Dontu G, Ince TA. Of mice and women: A comparative tissue biology perspective of breast stem cells and differentiation. J Mammary Gland Biol Neoplasia 20: 51‐62, 2015.
 99.Dudley AC. Tumor endothelial cells. Cold Spring Harb Perspect Med 2: a006536, 2012.
 100.Dunleavey JM, Xiao L, Thompson J, Kim MM, Shields JM, Shelton SE, Irvin DM, Brings VE, Ollila DW, Brekken RA, Dayton PA, Melero‐Martin JM, Dudley AC. Vascular channels formed by subpopulations of PECAM1+ melanoma cells. Nat Commun 5: 5200, 2014.
 101.Dvorak HF. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650‐1659, 1986.
 102.Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20: 4368‐4380, 2002.
 103.Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: Implications for antiangiogenic tumor therapies. Cancer Res 60: 1388‐1393, 2000.
 104.Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune‐mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A 112: 1809‐1814, 2015.
 105.El‐Gohary YM, Metwally G, Saad RS, Robinson MJ, Mesko T, Poppiti RJ. Prognostic significance of intratumoral and peritumoral lymphatic density and blood vessel density in invasive breast carcinomas. Am J Clin Pathol 129: 578‐586, 2008.
 106.Elgazar‐Carmon V, Rudich A, Hadad N, Levy R. Neutrophils transiently infiltrate intra‐abdominal fat early in the course of high‐fat feeding. J Lipid Res 49: 1894‐1903, 2008.
 107.Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer 16: 447‐462, 2016.
 108.Eruslanov E, Daurkin I, Ortiz J, Vieweg J, Kusmartsev S. Pivotal Advance: Tumor‐mediated induction of myeloid‐derived suppressor cells and M2‐polarized macrophages by altering intracellular PGE(2) catabolism in myeloid cells. J Leukoc Biol 88: 839‐848, 2010.
 109.Escamilla J, Schokrpur S, Liu C, Priceman SJ, Moughon D, Jiang Z, Pouliot F, Magyar C, Sung JL, Xu J, Deng G, West BL, Bollag G, Fradet Y, Lacombe L, Jung ME, Huang J, Wu L. CSF1 receptor targeting in prostate cancer reverses macrophage‐mediated resistance to androgen blockade therapy. Cancer Res 75: 950‐962, 2015.
 110.Escobedo N, Proulx ST, Karaman S, Dillard ME, Johnson N, Detmar M, Oliver G. Restoration of lymphatic function rescues obesity in Prox1‐haploinsufficient mice. JCI Insight 1: pii: e85096, 2016.
 111.Ewertz M, Jensen M‐B, Gunnarsdóttir KÁ, Højris I, Jakobsen EH, Nielsen D, Stenbygaard LE, Tange UB, Cold S. Effect of obesity on prognosis after early‐stage breast cancer. J Clin Oncol 29: 25‐31, 2011.
 112.Fain JN, Bahouth SW, Madan AK. TNFalpha release by the nonfat cells of human adipose tissue. Int J Obes Relat Metab Disord 28: 616‐622, 2004.
 113.Fernandez‐Garcia B, Eiro N, Miranda MA, Cid S, Gonzalez LO, Dominguez F, Vizoso FJ. Prognostic significance of inflammatory factors expression by stroma from breast carcinomas. Carcinogenesis 37: 768‐776, 2016.
 114.Ferrante AW. The immune cells in adipose tissue. Diabetes Obes Metab 15: 34‐38, 2013.
 115.Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 9: 669‐676, 2003.
 116.Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15: 930‐939, 2009.
 117.Finley DS, Calvert VS, Inokuchi J, Lau A, Narula N, Petricoin EF, Zaldivar F, Santos R, Tyson DR, Ornstein DK. Periprostatic adipose tissue as a modulator of prostate cancer aggressiveness. J Urol 182: 1621‐1627, 2009.
 118.Fisher DT, Appenheimer MM, Evans SS. The two faces of IL‐6 in the tumor microenvironment. Semin Immunol 26: 38‐47, 2014.
 119.Flammiger A, Weisbach L, Huland H, Tennstedt P, Simon R, Minner S, Bokemeyer C, Sauter G, Schlomm T, Trepel M. High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer. Eur J Cancer 49: 1273‐1279, 2013.
 120.Flegal KM, Kruszon‐Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 315: 2284‐2291, 2016.
 121.Fleischmann A, Schlomm T, Kollermann J, Sekulic N, Huland H, Mirlacher M, Sauter G, Simon R, Erbersdobler A. Immunological microenvironment in prostate cancer: High mast cell densities are associated with favorable tumor characteristics and good prognosis. The Prostate 69: 976‐981, 2009.
 122.Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330‐336, 2003.
 123.Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, Harris AL. Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53: 4161‐4163, 1993.
 124.Fox SB, Generali DG, Harris AL. Breast tumour angiogenesis. Breast Cancer Res 9: 1‐11, 2007.
 125.Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, Pamer EG, Li MO. The cellular and molecular origin of tumor‐associated macrophages. Science 344: 921‐925, 2014.
 126.Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci 123: 4195‐4200, 2010.
 127.Freedland SJ, Aronson WJ. Examining the relationship between obesity and prostate cancer. Rev Urol 6: 73‐81, 2004.
 128.Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha‐Hicks P, Rathmell JC, Makowski L. Metabolic reprogramming of macrophages: Glucose transporter 1 (GLUT1)‐mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem 289: 7884‐7896, 2014.
 129.Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM. Polarization of tumor‐associated neutrophil phenotype by TGF‐beta: “N1” versus “N2” TAN. Cancer Cell 16: 183‐194, 2009.
 130.Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin‐6: Depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83: 847‐850, 1998.
 131.Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet‐induced obese mice. Diabetes 58: 2574‐2582, 2009.
 132.Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand‐Rosenberg S, Schreiber H. The terminology issue for myeloid‐derived suppressor cells. Cancer Res 67: 425‐426, 2007.
 133.Gabrilovich DI, Nagaraj S. Myeloid‐derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9: 162‐174, 2009.
 134.Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: Recent advances. Annu Rev Immunol 23: 749‐786, 2005.
 135.Gao P, Zhou GY, Yin G, Liu Y, Liu ZY, Zhang J, Hao CY. Lymphatic vessel density as a prognostic indicator for patients with stage I cervical carcinoma. Hum Pathol 37: 719‐725, 2006.
 136.Garcia Nores GD, Cuzzone DA, Albano NJ, Hespe GE, Kataru RP, Torrisi JS, Gardenier JC, Savetsky IL, Aschen SZ, Nitti MD, Mehrara BJ. Obesity but not high‐fat diet impairs lymphatic function. Int J Obes (Lond) 40: 1582‐1590, 2016.
 137.Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol 207: 12‐22, 2006.
 138.Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma'ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ. Gene expression profiles and transcriptional regulatory pathways underlying mouse tissue macrophage identity and diversity. Nat Immunol 13: 1118‐1128, 2012.
 139.Gazi E, Gardner P, Lockyer NP, Hart CA, Brown MD, Clarke NW. Direct evidence of lipid translocation between adipocytes and prostate cancer cells with imaging FTIR microspectroscopy. J Lipid Res 48: 1846‐1856, 2007.
 140.Gehmert S, Gehmert S, Prantl L, Vykoukal J, Alt E, Song YH. Breast cancer cells attract the migration of adipose tissue‐derived stem cells via the PDGF‐BB/PDGFR‐beta signaling pathway. Biochem Biophys Res Commun 398: 601‐605, 2010.
 141.Ghajar CM, Bissell MJ. Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: Insights from imaging. Histochem Cell Biol 130: 1105‐1118, 2008.
 142.Ghosh S, Hughes D, Parma DL, Ramirez A, Li R. Association of obesity and circulating adipose stromal cells among breast cancer survivors. Mol Biol Rep 41: 2907‐2916, 2014.
 143.Gillespie EF, Sorbero ME, Hanauer DA, Sabel MS, Herrmann EJ, Weiser LJ, Jagielski CH, Griggs JJ. Obesity and angiolymphatic invasion in primary breast cancer. Ann Surg Oncol 17: 752‐759, 2010.
 144.Ginhoux F, Guilliams M. Tissue‐resident macrophage ontogeny and homeostasis. Immunity 44: 439‐449, 2016.
 145.Gioulbasanis I, Martin L, Baracos VE, Thezenas S, Koinis F, Senesse P. Nutritional assessment in overweight and obese patients with metastatic cancer: Does it make sense? Ann Oncol 26: 217‐221, 2015.
 146.Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: A consensus report. Diabetes Care 33: 1674‐1685, 2010.
 147.Giralt M, Villarroya F. White, brown, beige/brite: Different adipose cells for different functions? Endocrinology 154: 2992‐3000, 2013.
 148.Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR. Tissue‐resident macrophages originate from yolk‐sac‐derived erythro‐myeloid progenitors. Nature 518: 547‐551, 2015.
 149.Gonzalez MC, Pastore CA, Orlandi SP, Heymsfield SB. Obesity paradox in cancer: New insights provided by body composition. Am J Clin Nutr 99: 999‐1005, 2014.
 150.Gordon S. The macrophage: Past, present and future. Eur J Immunol 37(Suppl 1): S9‐S17, 2007.
 151.Grabowska MM, DeGraff DJ, Yu X, Jin RJ, Chen Z, Borowsky AD, Matusik RJ. Mouse models of prostate cancer: Picking the best model for the question. Cancer Metastasis Rev 33: 377‐397, 2014.
 152.Green JE, Shibata M‐A, Yoshidome K, Liu M‐l, Jorcyk C, Anver MR, Wigginton J, Wiltrout R, Shibata E, Kaczmarczyk S. The C3 (1)/SV40 T‐antigen transgenic mouse model of mammary cancer: Ductal epithelial cell targeting with multistage progression to carcinoma. Oncogene 19: 1020‐1027, 2000.
 153.Gu J‐W, Young E, Patterson SG, Makey KL, Wells J, Huang M, Tucker KB, Miele L. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice. Cancer Biol Ther 11: 910‐917, 2011.
 154.Haase J, Weyer U, Immig K, Kloting N, Bluher M, Eilers J, Bechmann I, Gericke M. Local proliferation of macrophages in adipose tissue during obesity‐induced inflammation. Diabetologia 57: 562‐571, 2014.
 155.Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE. Regulation of macrophage function in tumors: The multifaceted role of NF‐kappaB. Blood 113: 3139‐3146, 2009.
 156.Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR. “Re‐educating” tumor‐associated macrophages by targeting NF‐kappaB. J Exp Med 205: 1261‐1268, 2008.
 157.Hakanpaa L, Sipila T, Leppanen VM, Gautam P, Nurmi H, Jacquemet G, Eklund L, Ivaska J, Alitalo K, Saharinen P. Endothelial destabilization by angiopoietin‐2 via integrin beta1 activation. Nat Commun 6: 5962, 2015.
 158.Halberg N, Khan T, Trujillo ME, Wernstedt‐Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner‐Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE. Hypoxia‐inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 29: 4467‐4483, 2009.
 159.Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353‐364, 1996.
 160.Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 144: 646‐674, 2011.
 161.Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Bone marrow fat: Linking adipocyte‐induced inflammation with skeletal metastases. Cancer Metastasis Rev 33: 527‐543, 2014.
 162.Harms M, Seale P. Brown and beige fat: Development, function and therapeutic potential. Nat Med 19: 1252‐1263, 2013.
 163.Harvey NL, Srinivasan RS, Dillard ME, Johnson NC, Witte MH, Boyd K, Sleeman MW, Oliver G. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult‐onset obesity. Nat Genet 37: 1072‐1081, 2005.
 164.Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia‐Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue‐resident macrophages self‐maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38: 792‐804, 2013.
 165.Hattori Y, Hattori K, Hayashi T. Pleiotropic benefits of metformin: Macrophage targeting its anti‐inflammatory mechanisms. Diabetes 64: 1907‐1909, 2015.
 166.Hausman GJ, Richardson RL. Adipose tissue angiogenesis. J Anim Sci 82: 925‐934, 2004.
 167.He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen MJ, Haiko P, Salven P, Alitalo K. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 64: 3737‐3740, 2004.
 168.Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell 1: 467‐475, 2001.
 169.Herroon MK, Rajagurubandara E, Hardaway AL, Powell K, Turchick A, Feldmann D, Podgorski I. Bone marrow adipocytes promote tumor growth in bone via FABP4‐dependent mechanisms. Oncotarget 4: 2108‐2123, 2013.
 170.Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8: R76, 2007.
 171.Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton‐Piallat ML, Gabbiani G. The myofibroblast: One function, multiple origins. Am J Pathol 170: 1807‐1816, 2007.
 172.Hiratsuka A, Adachi H, Fujiura Y, Yamagishi S‐I, Hirai Y, Enomoto M, Satoh A, Hino A, Furuki K, Imaizumi T. Strong association between serum hepatocyte growth factor and metabolic syndrome. J Clin Endocrinol Metab 90: 2927‐2931, 2005.
 173.Ho‐Yen CM, Green AR, Rakha EA, Brentnall AR, Ellis IO, Kermorgant S. C‐Met in invasive breast cancer: Is there a relationship with the basal‐like subtype? Cancer 120: 163‐171, 2014.
 174.Ho‐Yen CM, Jones JL, Kermorgant S. The clinical and functional significance of c‐Met in breast cancer: A review. Breast Cancer Res 17: 1‐11, 2015.
 175.Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057‐1061, 2003.
 176.Hovey RC, Aimo L. Diverse and active roles for adipocytes during mammary gland growth and function. J Mammary Gland Biol Neoplasia 15: 279‐290, 2010.
 177.Huber J, Kiefer FW, Zeyda M, Ludvik B, Silberhumer GR, Prager G, Zlabinger GJ, Stulnig TM. CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity. J Clin Endocrinol Metab 93: 3215‐3221, 2008.
 178.Huo CW, Chew G, Hill P, Huang D, Ingman W, Hodson L, Brown KA, Magenau A, Allam AH, McGhee E, Timpson P, Henderson MA, Thompson EW, Britt K. High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. Breast Cancer Res 17: 79, 2015.
 179.Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, Ng MR, Nia HT, Grahovac J, Kao S, Babykutty S, Huang Y, Jung K, Rahbari NN, Han X, Chauhan VP, Martin JD, Kahn J, Huang P, Desphande V, Michaelson J, Michelakos TP, Ferrone CR, Soares R, Boucher Y, Fukumura D, Jain RK. Obesity‐induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov 6: 852‐869, 2016.
 180.Inman JL, Robertson C, Mott JD, Bissell MJ. Mammary gland development: Cell fate specification, stem cells and the microenvironment. Development 142: 1028‐1042, 2015.
 181.Irani AA, Schechter NM, Craig SS, DeBlois G, Schwartz LB. Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci U S A 83: 4464‐4468, 1986.
 182.Ishijima Y, Ohmori S, Ohneda K. Mast cell deficiency results in the accumulation of preadipocytes in adipose tissue in both obese and non‐obese mice. FEBS Open Bio 4: 18‐24, 2013.
 183.Ito Y, Ishiguro H, Kobayashi N, Hasumi H, Watanabe M, Yao M, Uemura H. Adipocyte‐derived monocyte chemotactic protein‐1 (MCP‐1) promotes prostate cancer progression through the induction of MMP‐2 activity. The Prostate 75: 1009‐1019, 2015.
 184.Ittmann M, Huang J, Radaelli E, Martin P, Signoretti S, Sullivan R, Simons BW, Ward JM, Robinson BD, Chu GC, Loda M, Thomas G, Borowsky A, Cardiff RD. Animal models of human prostate cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res 73: 2718‐2736, 2013.
 185.Iyengar P, Combs TP, Shah SJ, Gouon‐Evans V, Pollard JW, Albanese C, Flanagan L, Tenniswood MP, Guha C, Lisanti MP, Pestell RG, Scherer PE. Adipocyte‐secreted factors synergistically promote mammary tumorigenesis through induction of anti‐apoptotic transcriptional programs and proto‐oncogene stabilization. Oncogene 22: 6408‐6423, 2003.
 186.Iyengar P, Espina V, Williams TW, Lin Y, Berry D, Jelicks LA, Lee H, Temple K, Graves R, Pollard J, Chopra N, Russell RG, Sasisekharan R, Trock BJ, Lippman M, Calvert VS, Petricoin EF, 3rd, Liotta L, Dadachova E, Pestell RG, Lisanti MP, Bonaldo P, Scherer PE. Adipocyte‐derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115: 1163‐1176, 2005.
 187.Johansson A, Rudolfsson S, Hammarsten P, Halin S, Pietras K, Jones J, Stattin P, Egevad L, Granfors T, Wikstrom P, Bergh A. Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. Am J Pathol 177: 1031‐1041, 2010.
 188.Johnson AR, Milner JJ, Makowski L. The inflammation highway: Metabolism accelerates inflammatory traffic in obesity. Immunol Rev 249: 218‐238, 2012.
 189.Johnson AR, Qin Y, Cozzo AJ, Freemerman AJ, Huang MJ, Zhao L, Sampey BP, Milner JJ, Beck MA, Damania B, Rashid N, Galanko JA, Lee DP, Edin ML, Zeldin DC, Fueger PT, Dietz B, Stahl A, Wu Y, Mohlke KL, Makowski L. Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5: 506‐526, 2016.
 190.Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30: 531‐564, 2012.
 191.Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, Elliott MR, Gruber F, Han J, Chen W, Kensler T, Ravichandran KS, Isakson BE, Wamhoff BR, Leitinger N. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 107: 737‐746, 2010.
 192.Kapoor J, Namdarian B, Pedersen J, Hovens C, Moon D, Peters J, Costello AJ, Ruljancich P, Corcoran NM. Extraprostatic extension into periprostatic fat is a more important determinant of prostate cancer recurrence than an invasive phenotype. J Urol 190: 2061‐2066, 2013.
 193.Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. Cancer‐associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res 10: 1403‐1418, 2012.
 194.Karaman S, Hollmen M, Robciuc MR, Alitalo A, Nurmi H, Morf B, Buschle D, Alkan HF, Ochsenbein AM, Alitalo K, Wolfrum C, Detmar M. Blockade of VEGF‐C and VEGF‐D modulates adipose tissue inflammation and improves metabolic parameters under high‐fat diet. Mol Metab 4: 93‐105, 2015.
 195.Karlsson EA, Beck MA. The burden of obesity on infectious disease. Exp Biol Med (Maywood) 235: 1412‐1424, 2010.
 196.Kelesidis I, Kelesidis T, Mantzoros CS. Adiponectin and cancer: A systematic review. Br J Cancer 94: 1221‐1225, 2006.
 197.Keto CJ, Aronson WJ, Terris MK, Presti JC, Kane CJ, Amling CL, Freedland SJ. Obesity is associated with castration‐resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: Results from the SEARCH database. BJU Int 110: 492‐498, 2012.
 198.Khamis ZI, Sahab ZJ, Sang QX. Active roles of tumor stroma in breast cancer metastasis. Int J Breast Cancer 2012: 574025, 2012.
 199.Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer PE. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 29: 1575‐1591, 2009.
 200.Kidd S, Spaeth E, Watson K, Burks J, Lu H, Klopp A, Andreeff M, Marini FC. Origins of the tumor microenvironment: Quantitative assessment of adipose‐derived and bone marrow‐derived stroma. PLoS One 7: e30563, 2012.
 201.Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, Spiegelman BM. Tumour‐derived PTH‐related protein triggers adipose tissue browning and cancer cachexia. Nature 513: 100‐104, 2014.
 202.Knaapen AM, Gungor N, Schins RP, Borm PJ, Van Schooten FJ. Neutrophils and respiratory tract DNA damage and mutagenesis: a review. Mutagenesis 21: 225‐236, 2006.
 203.Kobayashi H, DeBusk LM, Lin PC. Angiopoietin/Tie2 signaling regulates tumor angiogenesis. In: Teicher BA, Ellis LM, editors. Antiangiogenic Agents in Cancer Therapy. Totowa, NJ: Humana Press, 2008, pp. 171‐187.
 204.Kolle SF, Fischer‐Nielsen A, Mathiasen AB, Elberg JJ, Oliveri RS, Glovinski PV, Kastrup J, Kirchhoff M, Rasmussen BS, Talman ML, Thomsen C, Dickmeiss E, Drzewiecki KT. Enrichment of autologous fat grafts with ex‐vivo expanded adipose tissue‐derived stem cells for graft survival: a randomised placebo‐controlled trial. Lancet 382: 1113‐1120, 2013.
 205.Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, Kuzma JN, Larson I, Billing PS, Landerholm RW, Crouthamel M, Gozal D, Hwang S, Singh PK, Becker L. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 20: 614‐625, 2014.
 206.Kristal AR, Gong Z. Obesity and prostate cancer mortality. Future Oncol 3: 557‐567, 2007.
 207.Kusmartsev S, Gabrilovich DI. STAT1 signaling regulates tumor‐associated macrophage‐mediated T cell deletion. J Immunol 174: 4880‐4891, 2005.
 208.Kyrgiou M, Kalliala I, Markozannes G, Gunter MJ, Paraskevaidis E, Gabra H, Martin‐Hirsch P, Tsilidis KK. Adiposity and cancer at major anatomical sites: Umbrella review of the literature. BMJ (Clinical research ed) 356: j477, 2017.
 209.Landskroner‐Eiger S, Park J, Israel D, Pollard JW, Scherer PE. Morphogenesis of the developing mammary gland: Stage‐dependent impact of adipocytes. Dev Biol 344: 968‐978, 2010.
 210.Lauby‐Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K. Body fatness and cancer–‐viewpoint of the IARC Working Group. N Engl J Med 375: 794‐798, 2016.
 211.Laurent V, Guerard A, Mazerolles C, Le Gonidec S, Toulet A, Nieto L, Zaidi F, Majed B, Garandeau D, Socrier Y, Golzio M, Cadoudal T, Chaoui K, Dray C, Monsarrat B, Schiltz O, Wang YY, Couderc B, Valet P, Malavaud B, Muller C. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nat Commun 7: 10230, 2016.
 212.Lavin Y, Mortha A, Rahman A, Merad M. Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol 15: 731‐744, 2015.
 213.Lawrence T, Fong C. The resolution of inflammation: Anti‐inflammatory roles for NF‐kappaB. Int J Biochem Cell Biol 42: 519‐523, 2010.
 214.Lawrence T, Gilroy DW, Colville‐Nash PR, Willoughby DA. Possible new role for NF‐kappaB in the resolution of inflammation. Nat Med 7: 1291‐1297, 2001.
 215.Lazar I, Clement E, Dauvillier S, Milhas D, Ducoux‐Petit M, LeGonidec S, Moro C, Soldan V, Dalle S, Balor S, Golzio M, Burlet‐Schiltz O, Valet P, Muller C, Nieto L. Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: A novel mechanism linking obesity and cancer. Cancer Res 76: 4051‐4057, 2016.
 216.Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: Implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med 34: 1‐11, 2013.
 217.Lee TJ, Bhang SH, Yang HS, La WG, Yoon HH, Shin JY, Seong JY, Shin H, Kim BS. Enhancement of long‐term angiogenic efficacy of adipose stem cells by delivery of FGF2. Microvasc Res 84: 1‐8, 2012.
 218.Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56: 4625‐4629, 1996.
 219.Lennon H, Sperrin M, Badrick E, Renehan AG. The obesity paradox in cancer: A review. Curr Oncol Rep 18: 56: 2016.
 220.Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139: 891‐906, 2009.
 221.Li P, Lu M, Nguyen MT, Bae EJ, Chapman J, Feng D, Hawkins M, Pessin JE, Sears DD, Nguyen AK, Amidi A, Watkins SM, Nguyen U, Olefsky JM. Functional heterogeneity of CD11c‐positive adipose tissue macrophages in diet‐induced obese mice. J Biol Chem 285: 15333‐15345, 2010.
 222.Li X, Loberg R, Liao J, Ying C, Snyder LA, Pienta KJ, McCauley LK. A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res 69: 1685‐1692, 2009.
 223.Li Z, Chen L, Qin Z. Paradoxical roles of IL‐4 in tumor immunity. Cell Mol Immunol 6: 415‐422, 2009.
 224.Ligibel JA, Alfano CM, Courneya KS, Demark‐Wahnefried W, Burger RA, Chlebowski RT, Fabian CJ, Gucalp A, Hershman DL, Hudson MM, Jones LW, Kakarala M, Ness KK, Merrill JK, Wollins DS, Hudis CA. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol 32: 3568‐3574, 2014.
 225.Lijnen HR. Angiogenesis and obesity. Cardiovasc Res 78: 286‐293, 2008.
 226.Lim S, Hosaka K, Nakamura M, Cao Y. Co‐option of pre‐existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis. Oncotarget. 7(25): 38282‐38291, 2016.
 227.Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66: 11238‐11246, 2006.
 228.Liu J, Divoux A, Sun J, Zhang J, Clément K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP. Deficiency and pharmacological stabilization of mast cells reduce diet‐induced obesity and diabetes in mice. Nat Med 15: 940‐945, 2009.
 229.Loi S, Milne RL, Friedlander ML, McCredie MR, Giles GG, Hopper JL, Phillips KA. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 14: 1686‐1691, 2005.
 230.Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression. J Cell Biol 196: 395‐406, 2012.
 231.Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175‐184, 2007.
 232.Madge LA, May MJ. Classical NF‐kappaB activation negatively regulates noncanonical NF‐kappaB‐dependent CXCL12 expression. J Biol Chem 285: 38069‐38077, 2010.
 233.Mangia A, Malfettone A, Rossi R, Paradiso A, Ranieri G, Simone G, Resta L. Tissue remodelling in breast cancer: Human mast cell tryptase as an initiator of myofibroblast differentiation. Histopathology 58: 1096‐1106, 2011.
 234.Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ. Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Pathol 155: 739‐752, 1999.
 235.Mantovani A, Allavena P. The interaction of anticancer therapies with tumor‐associated macrophages. J Exp Med 212: 435‐445, 2015.
 236.Mantovani A, Sica A, Allavena P, Garlanda C, Locati M. Tumor‐associated macrophages and the related myeloid‐derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol 70: 325‐330, 2009.
 237.Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: Tumor‐associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549‐555, 2002.
 238.Marech I, Ammendola M, Sacco R, Capriuolo GS, Patruno R, Rubini R, Luposella M, Zuccala V, Savino E, Gadaleta CD, Ribatti D, Ranieri G. Serum tryptase, mast cells positive to tryptase and microvascular density evaluation in early breast cancer patients: Possible translational significance. BMC Cancer 14: 534, 2014.
 239.Mariman EC, Wang P. Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci 67: 1277‐1292, 2010.
 240.Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, Murphy R, Ghosh S, Sawyer MB, Baracos VE. Cancer cachexia in the age of obesity: Skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 31: 1539‐1547, 2013.
 241.Martinez‐Outschoorn UE, Sotgia F, Lisanti MP. Power surge: Supporting cells “fuel” cancer cell mitochondria. Cell Metab 15: 4‐5, 2012.
 242.Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Reports 6: 13: 2014.
 243.Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte‐to‐macrophage differentiation and polarization: New molecules and patterns of gene expression. J Immunol 177: 7303‐7311, 2006.
 244.Mass E, Ballesteros I, Farlik M, Halbritter F, Günther P, Crozet L, Jacome‐Galarza CE, Händler K, Klughammer J, Kobayashi Y, Gomez‐Perdiguero E, Schultze JL, Beyer M, Bock C, Geissmann F. Specification of tissue‐resident macrophages during organogenesis. Science 353: aaf4238, 2016.
 245.Massa M, Gasparini S, Baldelli I, Scarabelli L, Santi P, Quarto R, Repaci E. Interaction between breast cancer cells and adipose tissue cells derived from fat grafting. Aesthet Surg J 36: 358‐363, 2016.
 246.Mayi TH, Daoudi M, Derudas B, Gross B, Bories G, Wouters K, Brozek J, Caiazzo R, Raverdi V, Pigeyre M, Allavena P, Mantovani A, Pattou F, Staels B, Chinetti‐Gbaguidi G. Human adipose tissue macrophages display activation of cancer‐related pathways. J Biol Chem 287: 21904‐21913, 2012.
 247.Mazzarella L, Disalvatore D, Bagnardi V, Rotmensz N, Galbiati D, Caputo S, Curigliano G, Pelicci PG. Obesity increases the incidence of distant metastases in oestrogen receptor‐negative human epidermal growth factor receptor 2‐positive breast cancer patients. Eur J Cancer 49: 3588‐3597, 2013.
 248.McIntyre A, Harris AL. Metabolic and hypoxic adaptation to anti‐angiogenic therapy: A target for induced essentiality. EMBO Mol Med 7: 368‐379, 2015.
 249.Mestak O, Hromadkova V, Fajfrova M, Molitor M, Mestak J. Evaluation of oncological safety of fat grafting after breast‐conserving therapy: A prospective study. Ann Surg Oncol 23: 776‐781, 2016.
 250.Meyer KA, Neeley CK, Baker NA, Washabaugh AR, Flesher CG, Nelson BS, Frankel TL, Lumeng CN, Lyssiotis CA, Wynn ML, Rhim AD, O'Rourke RW. Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer. Biochem Biophys Rep 7: 144‐149, 2016.
 251.Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis & Tissue Repair 5: S5, 2012.
 252.Miyake H, Hara I, Eto H. Serum level of cathepsin B and its density in men with prostate cancer as novel markers of disease progression. Anticancer Res 24: 2573‐2577, 2004.
 253.Miyazawa‐Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia 46: 1483‐1488, 2003.
 254.Miyazawa‐Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia 46: 1483‐1488, 2003.
 255.Mizuno S, Nakamura T. HGF‐MET cascade, a key target for inhibiting cancer metastasis: The impact of NK4 discovery on cancer biology and therapeutics. Int J Mol Sci 14: 888‐919, 2013.
 256.Mohammed RA, Ellis IO, Mahmmod AM, Hawkes EC, Green AR, Rakha EA, Martin SG. Lymphatic and blood vessels in basal and triple‐negative breast cancers: Characteristics and prognostic significance. Mod Pathol 24: 774‐785, 2011.
 257.Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210: 535‐549, 2013.
 258.Moorman AM, Vink R, Heijmans HJ, van der Palen J, Kouwenhoven EA. The prognostic value of tumour‐stroma ratio in triple‐negative breast cancer. Eur J Surg Oncol 38: 307‐313, 2012.
 259.Moreira Â, Pereira SS, Machado CL, Morais T, Costa M, Monteiro MP. Obesity inhibits lymphangiogenesis in prostate tumors. Int J Clin Exp Pathol 7: 348‐352, 2014.
 260.Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, Du B, Brogi E, Crawford CB, Kopelovich L, Subbaramaiah K, Dannenberg AJ. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4: 1021‐1029, 2011.
 261.Moscat J, Diaz‐Meco MT. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 137: 1001‐1004, 2009.
 262.Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958‐969, 2008.
 263.Moumen M, Chiche A, Cagnet S, Petit V, Raymond K, Faraldo MM, Deugnier MA, Glukhova MA. The mammary myoepithelial cell. Int J Dev Biol 55: 763‐771, 2011.
 264.Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In't Veld P, De Baetselier P, Van Ginderachter JA. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70: 5728‐5739, 2010.
 265.Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S. Dead adipocytes, detected as crown‐like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 49: 1562‐1568, 2008.
 266.Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8: 618‐631, 2008.
 267.Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 41: 14‐20, 2014.
 268.Nakajima EC, Van Houten B. Metabolic symbiosis in cancer: refocusing the Warburg lens. Mol Carcinog 52: 329‐337, 2013.
 269.Nakajima S, Koh V, Kua LF, So J, Davide L, Lim KS, Petersen SH, Yong WP, Shabbir A, Kono K. Accumulation of CD11c+CD163+ adipose tissue macrophages through upregulation of intracellular 11beta‐HSD1 in human obesity. J Immunol 197: 3735‐3745, 2016.
 270.NCD Risk Factor Collaboration (NCD‐RisC) a. Trends in adult body‐mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population‐based measurement studies with 19.2 million participants. Lancet 387: 1377‐1396, 2016.
 271.Nelson CM, Bissell MJ. Of extracellular matrix, scaffolds, and signaling: Tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 22: 287‐309, 2006.
 272.Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, Ochs‐Balcom HM, Thomson CA, Caan BJ, Tinker LF, Urrutia RP, Knudtson J, Anderson GL. Overweight, obesity, and postmenopausal invasive breast cancer risk: A secondary analysis of the Women's Health Initiative Randomized Clinical Trials. JAMA Oncol 1: 611‐621, 2015.
 273.Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell‐Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17: 1498‐1503, 2011.
 274.Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tissue and adipocytes supports tumorigenesis and metastasis(). Biochim Biophys Acta 1831: 1533‐1541, 2013.
 275.Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 127: 759‐767, 2010.
 276.Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914‐920, 2009.
 277.Nishimura S, Manabe I, Nagasaki M, Seo K, Yamashita H, Hosoya Y, Ohsugi M, Tobe K, Kadowaki T, Nagai R. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J Clin Invest 118: 710‐721, 2008.
 278.Noffz G, Qin Z, Kopf M, Blankenstein T. Neutrophils but not eosinophils are involved in growth suppression of IL‐4‐secreting tumors. J Immunol 160: 345‐350, 1998.
 279.Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S. PD‐L1 is a novel direct target of HIF‐1alpha, and its blockade under hypoxia enhanced MDSC‐mediated T cell activation. J Exp Med 211: 781‐790, 2014.
 280.Nonomura N, Takayama H, Nishimura K, Oka D, Nakai Y, Shiba M, Tsujimura A, Nakayama M, Aozasa K, Okuyama A. Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer. Br J Cancer 97: 952‐956, 2007.
 281.Nores GD, Cuzzone DA, Albano NJ, Hespe GE, Kataru RP, Torrisi JS, Gardenier JC, Savetsky IL, Aschen SZ, Nitti MD, Mehrara BJ. Obesity but not high‐fat diet impairs lymphatic function. Int J Obes (Lond) 40: 1582‐1590, 2016.
 282.Nozawa H, Chiu C, Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 103: 12493‐12498, 2006.
 283.O'Malley RL, Taneja SS. Obesity and prostate cancer. Can J Urol 13(Suppl 2): 11‐17, 2006.
 284.Obeid S, Hebbard L. Role of adiponectin and its receptors in cancer. Cancer Biol Med 9: 213‐220, 2012.
 285.Ochoa AC, Zea AH, Hernandez C, Rodriguez PC. Arginase, prostaglandins, and myeloid‐derived suppressor cells in renal cell carcinoma. Clin Cancer Res 13: 721s‐726s, 2007.
 286.Oft M. IL‐10: Master switch from tumor‐promoting inflammation to antitumor immunity. Cancer Immunol Res 2: 194‐199, 2014.
 287.Ogden CL, Carroll MD, Lawman HG, Fryar CD, Kruszon‐Moran D, Kit BK, Flegal KM. Trends in obesity prevalence among children and adolescents in the United States, 1988‐1994 through 2013‐2014. JAMA 315: 2292‐2299, 2016.
 288.Ojalvo LS, King W, Cox D, Pollard JW. High‐density gene expression analysis of tumor‐associated macrophages from mouse mammary tumors. Am J Pathol 174: 1048‐1064, 2009.
 289.Okwan‐Duodu D, Umpierrez GE, Brawley OW, Diaz R. Obesity‐driven inflammation and cancer risk: Role of myeloid derived suppressor cells and alternately activated macrophages. Am J Cancer Res 3: 21‐33, 2013.
 290.Oliveira AG, Guabiraba R, Teixeira MM, Menezes GB. Tumor‐associated neutrophils. In: Trends in Stem Cell Proliferation and Cancer Research. Dordrecht, Netherlands: Springer, 2013, pp. 479‐501.
 291.Oliveira DSM, Dzinic S, Bonfil AI, Saliganan AD, Sheng S, Bonfil RD. The mouse prostate: A basic anatomical and histological guideline. Bosn J Basic Med Sci 16: 8‐13, 2016.
 292.Ortega Martinez de Victoria E, Xu X, Koska J, Francisco AM, Scalise M, Ferrante AW, Krakoff J. Macrophage content in subcutaneous adipose tissue: Associations with adiposity, age, inflammatory markers, and whole‐body insulin action in healthy Pima Indians. Diabetes 58: 385‐393, 2009.
 293.Ortega RA, Barham W, Sharman K, Tikhomirov O, Giorgio TD, Yull FE. Manipulating the NF‐κB pathway in macrophages using mannosylated, siRNA‐delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions. Int J Nanomedicine 11: 2163‐2177, 2016.
 294.Osman MA, Hennessy BT. Obesity correlation with metastases development and response to first‐line metastatic chemotherapy in breast cancer. Clin Med Insights Oncol 9: 105‐112, 2015.
 295.Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296: 1883‐1886, 2002.
 296.Paich HA, Sheridan, PA, Handy J, Karlsson EA, Schultz‐Cherry S, Hudgens MG, Noah TL, Weir SS, Beck MA. Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus. Obesity (Silver Spring) 21: 2377‐2386, 2013.
 297.Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer–‐mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol 10: 455‐465, 2014.
 298.Park J, Morley TS, Scherer PE. Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. EMBO Mol Med 5: 935‐948, 2013.
 299.Park J, Scherer PE. Leptin and cancer: From cancer stem cells to metastasis. Endocr Relat Cancer 18: C25‐C29, 2011.
 300.Park J, Scherer PE. Adipocyte‐derived endotrophin promotes malignant tumor progression. J Clin Invest 122: 4243‐4256, 2012.
 301.Pasarica M, Gowronska‐Kozak B, Burk D, Remedios I, Hymel D, Gimble J, Ravussin E, Bray GA, Smith SR. Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab 94: 5155‐5162, 2009.
 302.Pasco JA, Holloway KL, Dobbins AG, Kotowicz MA, Williams LJ, Brennan SL. Body mass index and measures of body fat for defining obesity and underweight: A cross‐sectional, population‐based study. BMC Obesity 1: 9, 2014.
 303.Petruzzelli M, Schweiger M, Schreiber R, Campos‐Olivas R, Tsoli M, Allen J, Swarbrick M, Rose‐John S, Rincon M, Robertson G, Zechner R, Wagner EF. A switch from white to brown fat increases energy expenditure in cancer‐associated cachexia. Cell Metab 20: 433‐447, 2014.
 304.Phan SH. Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5: 334‐337, 2008.
 305.Piccard H, Muschel RJ, Opdenakker G. On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 82: 296‐309, 2012.
 306.Picon‐Ruiz M, Pan C, Drews‐Elger K, Jang K, Besser AH, Zhao D, Morata‐Tarifa C, Kim M, Ince TA, Azzam DJ, Wander SA, Wang B, Ergonul B, Datar RH, Cote RJ, Howard GA, El‐Ashry D, Torne‐Poyatos P, Marchal JA, Slingerland JM. Interactions between adipocytes and breast cancer cells stimulate cytokine production and drive Src/Sox2/miR‐302b‐mediated malignant progression. Cancer Res 76: 491‐504, 2016.
 307.Pierobon M, Frankenfeld CL. Obesity as a risk factor for triple‐negative breast cancers: A systematic review and meta‐analysis. Breast Cancer Res Treat 137: 307‐314, 2013.
 308.Poglio S, De Toni‐Costes F, Arnaud E, Laharrague P, Espinosa E, Casteilla L, Cousin B. Adipose tissue as a dedicated reservoir of functional mast cell progenitors. Stem Cells 28: 2065‐2072, 2010.
 309.Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen‐treated mice. J Neuroimmunol 170: 85‐92, 2005.
 310.Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol 84: 623‐630, 2008.
 311.Poschke I, Kiessling R. On the armament and appearances of human myeloid‐derived suppressor cells. Clin Immunol 144: 250‐268, 2012.
 312.Prima V, Kaliberova LN, Kaliberov S, Curiel DT, Kusmartsev S. COX2/mPGES1/PGE2 pathway regulates PD‐L1 expression in tumor‐associated macrophages and myeloid‐derived suppressor cells. Proc Natl Acad Sci U S A 114: 1117‐1122, 2017.
 313.Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. Matrix density‐induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK‐ERK linkage. Oncogene 28: 4326‐4343, 2009.
 314.Qian BZ, Li, J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard J. W. CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis. Nat Aust 475: 222‐225, 2011.
 315.Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 141: 39‐51, 2010.
 316.Qin Y, Sundaram S, Essaid L, Chen X, Miller SM, Yan F, Darr DB, Galanko JA, Montgomery SA, Major MB, Johnson GL, Troester MA, Makowski L. Weight loss reduces basal‐like breast cancer through kinome reprogramming. Cancer Cell Int 16: 26, 2016.
 317.Quail D, Joyce J. Microenvironmental regulation of tumor progression and metastasis. Nat Med 19: 1423‐1437, 2013.
 318.Raica M, Cimpean AM, Ceausu R, Ribatti D, Gaje P. Interplay between mast cells and lymphatic vessels in different molecular types of breast cancer. Anticancer Res 33: 957‐963, 2013.
 319.Rajput AB, Turbin DA, Cheang MC, Voduc DK, Leung S, Gelmon KA, Gilks CB, Huntsman DG. Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: A study of 4,444 cases. Breast Cancer Res Treat 107: 249‐257, 2008.
 320.Ramos Chaves M, Boleo‐Tome C, Monteiro‐Grillo I, Camilo M, Ravasco P. The diversity of nutritional status in cancer: New insights. Oncologist 15: 523‐530, 2010.
 321.Rapisarda A, Melillo G. Role of the hypoxic tumor microenvironment in the resistance to anti‐angiogenic therapies. Drug Resist Updat 12: 74‐80, 2009.
 322.Razzaghi H, Troester MA, Gierach GL, Olshan AF, Yankaskas BC, Millikan RC. Mammographic density and breast cancer risk in White and African American Women. Breast Cancer Res Treat 135: 571‐580, 2012.
 323.Religa P, Cao R, Bjorndahl M, Zhou Z, Zhu Z, Cao Y. Presence of bone marrow‐derived circulating progenitor endothelial cells in the newly formed lymphatic vessels. Blood 106: 4184‐4190, 2005.
 324.Ribatti D, Vacca A. Overview of angiogenesis during tumor growth. In: Angiogenesis. New York, NY: Springer, 2008, pp. 161‐168.
 325.Ribeiro AM, Andrade S, Pinho F, Monteiro JD, Costa M, Lopes C, Aguas AP, Monteiro MP. Prostate cancer cell proliferation and angiogenesis in different obese mice models. Int J Exp Pathol 91: 374‐386, 2010.
 326.Ribeiro R, Monteiro C, Cunha V, Oliveira M, Freitas M, Fraga A, Príncipe P, Lobato C, Lobo F, Morais A, Silva V, Sanches‐Magalhães J, Oliveira J, Pina F, Mota‐Pinto A, Lopes C, Medeiros R. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro. J Exp Clin Cancer Res 31: 32, 2012.
 327.Ribeiro R, Monteiro C, Silvestre R, Castela A, Coutinho H, Fraga A, Principe P, Lobato C, Costa C, Cordeiro‐da‐Silva A, Lopes JM, Lopes C, Medeiros R. Human periprostatic white adipose tissue is rich in stromal progenitor cells and a potential source of prostate tumor stroma. Exp Biol Med (Maywood) 237: 1155‐1162, 2012.
 328.Ribeiro RJ, Monteiro CP, Cunha VF, Azevedo AS, Oliveira MJ, Monteiro R, Fraga AM, Principe P, Lobato C, Lobo F, Morais A, Silva V, Sanches‐Magalhaes J, Oliveira J, Guimaraes JT, Lopes CM, Medeiros RM. Tumor cell‐educated periprostatic adipose tissue acquires an aggressive cancer‐promoting secretory profile. Cell Physiol Biochem 29: 233‐240, 2012.
 329.Rivera LB, Bergers G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol 36: 240‐249, 2015.
 330.Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC. Arginase I in myeloid suppressor cells is induced by COX‐2 in lung carcinoma. J Exp Med 202: 931‐939, 2005.
 331.Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, Antonia S, Ochoa JB, Ochoa AC. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T‐cell receptor expression and antigen‐specific T‐cell responses. Cancer Res 64: 5839‐5849, 2004.
 332.Rohm M, Schafer M, Laurent V, Ustunel BE, Niopek K, Algire C, Hautzinger O, Sijmonsma TP, Zota A, Medrikova D, Pellegata NS, Ryden M, Kulyte A, Dahlman I, Arner P, Petrovic N, Cannon B, Amri EZ, Kemp BE, Steinberg GR, Janovska P, Kopecky J, Wolfrum C, Bluher M, Berriel Diaz M, Herzig S. An AMP‐activated protein kinase‐stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat Med 22: 1120‐1130, 2016.
 333.Rupnick MA, Panigrahy D, Zhang C‐Y, Dallabrida SM, Lowell BB, Langer R, Folkman MJ. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A 99: 10730‐10735, 2002.
 334.Saad RS, Kordunsky L, Liu YL, Denning KL, Kandil HA, Silverman JF. Lymphatic microvessel density as prognostic marker in colorectal cancer. Mod Pathol 19: 1317‐1323, 2006.
 335.Sakkal S, Miller S, Apostolopoulos V, Nurgali K. Eosinophils in cancer: Favourable or unfavourable? Curr Med Chem 23: 650‐666, 2016.
 336.Samoszuk M, Corwin MA. Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer. Int J Cancer 107: 159‐163, 2003.
 337.Sampey BP, Freemerman AJ, Zhang J, Kuan PF, Galanko JA, O'Connell TM, Ilkayeva OR, Muehlbauer MJ, Stevens RD, Newgard CB, Brauer HA, Troester MA, Makowski L. Metabolomic profiling reveals mitochondrial‐derived lipid biomarkers that drive obesity‐associated inflammation. PloS One 7: e38812, 2012.
 338.Sampey BP, Vanhoose AM, Winfield HM, Freemerman AJ, Muehlbauer MJ, Fueger PT, Newgard CB, Makowski L. Cafeteria diet is a robust model of human metabolic syndrome with liver and adipose inflammation: Comparison to high‐fat diet. Obesity (Silver Spring) 19: 1109‐1117, 2011.
 339.Scapini P, Lapinet‐Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunol Rev 177: 195‐203, 2000.
 340.Schedin P, Keely PJ. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol 3: a003228, 2011.
 341.Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska‐Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, Goerdt S. Lymphatic endothelium‐specific hyaluronan receptor LYVE‐1 is expressed by stabilin‐1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 209: 67‐77, 2006.
 342.Schneider B. Randomized controlled trial of genomically girected therapy in patients with triple negative breast cancer. In: ClinicalTrials.gov identifier, NCT02101385, 2016.
 343.Schneider BP, Miller KD. Angiogenesis of breast cancer. J Clin Oncol 23: 1782‐1790, 2005.
 344.Seo BR, Bhardwaj P, Choi S, Gonzalez J, Andresen Eguiluz RC, Wang K, Mohanan S, Morris PG, Du B, Zhou XK, Vahdat LT, Verma A, Elemento O, Hudis CA, Williams RM, Gourdon D, Dannenberg AJ, Fischbach C. Obesity‐dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 7: 301ra130, 2015.
 345.Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7: 311‐317, 2006.
 346.Sestak I, Distler W, Forbes JF, Dowsett M, Howell A, Cuzick J. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: An exploratory analysis from the ATAC trial. J Clin Oncol 28: 3411‐3415, 2010.
 347.Shah NR, Braverman ER. Measuring adiposity in patients: The utility of body mass index (BMI), percent body fat, and leptin. PLoS One 7: e33308, 2012.
 348.Shao ZM, Nguyen M, Barsky SH. Human breast carcinoma desmoplasia is PDGF initiated. Oncogene 19: 4337‐4345, 2000.
 349.Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, Huang M, Batra RK, Dubinett SM. Tumor cyclooxygenase‐2/prostaglandin E2‐dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65: 5211‐5220, 2005.
 350.Shaul ME, Bennett G, Strissel KJ, Greenberg AS, Obin MS. Dynamic, M2‐like remodeling phenotypes of CD11c+ adipose tissue macrophages during high‐fat diet–induced obesity in mice. Diabetes 59: 1171‐1181, 2010.
 351.Sheen‐Chen SM, Liu YW, Eng HL, Chou FF. Serum levels of hepatocyte growth factor in patients with breast cancer. Cancer Epidemiol Biomarkers Prev 14: 715‐717, 2005.
 352.Shimizu Y, Shibata R, Shintani S, Ishii M, Murohara T. Therapeutic lymphangiogenesis with implantation of adipose‐derived regenerative cells. J Am Heart Assoc 1: e000877, 2012.
 353.Shimoda M, Mellody KT, Orimo A. Carcinoma‐associated fibroblasts are a rate‐limiting determinant for tumour progression. Semin Cell Dev Biol 21: 19‐25, 2010.
 354.Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, Yamamoto T, Anzai A, Isobe S, Yoshida N, Itoh H, Manabe I, Sekai M, Hamazaki Y, Fukuda K, Minato N, Sano M. Obesity accelerates T cell senescence in murine visceral adipose tissue. J Clin Invest 126: 4626‐4639, 2016.
 355.Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, Hu‐Lowe DD, Christensen JG. HGF/c‐Met acts as an alternative angiogenic pathway in sunitinib‐resistant tumors. Cancer Res 70: 10090‐10100, 2010.
 356.Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, Bell‐McGuinn KM, Zabor EC, Brogi E, Joyce JA. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25: 2465‐2479, 2011.
 357.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 65: 5‐29, 2015.
 358.Silha JV, Krsek M, Sucharda P, Murphy LJ. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond) 29: 1308‐1314, 2005.
 359.Sinha P, Clements VK, Fulton AM, Ostrand‐Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid‐derived suppressor cells. Cancer Res 67: 4507‐4513, 2007.
 360.Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF‐C promotes breast cancer metastasis. Nat Med 7: 192‐198, 2001.
 361.Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 3: 832‐844, 2003.
 362.Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 21: 698‐708, 2015.
 363.Spencer M, Yao‐Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, Peterson CA, Kern PA. Adipose tissue macrophages in insulin‐resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299: E1016‐E1027, 2010.
 364.Spessotto P, Dri P, Bulla R, Zabucchi G, Patriarca P. Human eosinophil peroxidase enhances tumor necrosis factor and hydrogen peroxide release by human monocyte‐derived macrophages. Eur J Immunol 25: 1366‐1373, 1995.
 365.Stewart DA, Cooper CR, Sikes RA. Changes in extracellular matrix (ECM) and ECM‐associated proteins in the metastatic progression of prostate cancer. Reprod Biol Endocrinol 2: 2, 2004.
 366.Strong AL, Semon JA, Strong TA, Santoke TT, Zhang S, McFerrin HE, Gimble JM, Bunnell BA. Obesity‐associated dysregulation of calpastatin and MMP‐15 in adipose‐derived stromal cells results in their enhanced invasion. Stem Cells 30: 2774‐2783, 2012.
 367.Strong AL, Strong TA, Rhodes LV, Semon JA, Zhang X, Shi Z, Zhang S, Gimble JM, Burow ME, Bunnell BA. Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways. Breast Cancer Res 15: R102, 2013.
 368.Strulov Shachar S, Williams GR. The obesity paradox in cancer‐moving beyond BMI. Cancer Epidemiol Biomarkers Prev 26: 13‐16, 2017.
 369.Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila) 4: 329‐346, 2011.
 370.Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D, Kopelovich L, Hudis CA, Dannenberg AJ. Increased levels of COX‐2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov 2: 356‐365, 2012.
 371.Sulpice E, Ding S, Muscatelli‐Groux B, Berge M, Han ZC, Plouet J, Tobelem G, Merkulova‐Rainon T. Cross‐talk between the VEGF‐A and HGF signalling pathways in endothelial cells. Biol Cell 101: 525‐539, 2009.
 372.Sun K, Park J, Gupta OT, Holland WL, Auerbach P, Zhang N, Goncalves Marangoni R, Nicoloro SM, Czech MP, Varga J, Ploug T, An Z, Scherer PE. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat Commun 5: 3485, 2014.
 373.Sun K, Tordjman J, Clément K, Scherer PE. Fibrosis and adipose tissue dysfunction. Cell Metab 18: 470‐477, 2013.
 374.Sun X, Casbas‐Hernandez P, Bigelow C, Makowski L, Joseph Jerry D, Smith Schneider S, Troester MA. Normal breast tissue of obese women is enriched for macrophage markers and macrophage‐associated gene expression. Breast Cancer Res Treat 131: 1003‐1012, 2012.
 375.Sundaram S, Freemerman AJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski L. Obesity‐mediated regulation of HGF/c‐Met is associated with reduced basal‐like breast cancer latency in parous mice. PLoS One 9: e111394, 2014.
 376.Sundaram S, Freemerman AJ, Johnson AR, Milner JJ, McNaughton KK, Galanko JA, Bendt KM, Darr DB, Perou CM, Troester MA, Makowski L. Role of HGF in obesity‐associated tumorigenesis: C3(1)‐TAg mice as a model for human basal‐like breast cancer. Breast Cancer Res Treat 142: 489‐503, 2013.
 377.Sundaram S, Le TL, Essaid L, Freemerman AJ, Huang MJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski L. Weight loss reversed obesity‐induced HGF/c‐Met pathway and basal‐like breast cancer progression. Front Oncol 4: 175, 2014.
 378.Sung MT, Eble JN, Cheng L. Invasion of fat justifies assignment of stage pT3a in prostatic adenocarcinoma. Pathology 38: 309‐311, 2006.
 379.Swierczynski J, Korczynska J, Goyke E, Adrych K, Raczynska S, Sledzinski Z. Serum hepatocyte growth factor concentration in obese women decreases after vertical banded gastroplasty. Obes Surg 15: 803‐808, 2005.
 380.Tabassum DP, Polyak K. Tumorigenesis: it takes a village. Nat Rev Cancer 15: 473‐483, 2015.
 381.Tahergorabi Z, Khazaei M. The relationship between inflammatory markers, angiogenesis, and obesity. ARYA Atheroscler 9: 247, 2013.
 382.Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self‐tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte‐associated antigen 4. J Exp Med 192: 303‐310, 2000.
 383.Takeda K, Sowa Y, Nishino K, Itoh K, Fushiki S. Adipose‐derived stem cells promote proliferation, migration, and tube formation of lymphatic endothelial cells in vitro by secreting lymphangiogenic factors. Ann Plast Surg 74: 728‐736, 2015.
 384.Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM. Neutrophils mediate insulin resistance in high fat diet fed mice via secreted elastase. Nat Med 18: 1407‐1412, 2012.
 385.Tam J, Duda DG, Perentes JY, Quadri RS, Fukumura D, Jain RK. Blockade of VEGFR2 and not VEGFR1 can limit diet‐induced fat tissue expansion: Role of local versus bone marrow‐derived endothelial cells. PLoS One 4: e4974, 2009.
 386.Tang KD, Liu J, Jovanovic L, An J, Hill MM, Vela I, Lee TK, Ma S, Nelson C, Russell PJ, Clements JA, Ling MT. Adipocytes promote prostate cancer stem cell self‐renewal through amplification of the cholecystokinin autocrine loop. Oncotarget 7: 4939‐4948, 2016.
 387.Taub DD, Longo DL. Insights into thymic aging and regeneration. Immunol Rev 205: 72‐93, 2005.
 388.Taylor CT. Interdependent roles for hypoxia inducible factor and nuclear factor‐κB in hypoxic inflammation. J Physiol 586: 4055‐4059, 2008.
 389.Tepper RI, Coffman RL, Leder P. An eosinophil‐dependent mechanism for the antitumor effect of interleukin‐4. Science 257: 548‐551, 1992.
 390.Theoharides TC, Conti P. Mast cells: The Jekyll and Hyde of tumor growth. Trends Immunol 25: 235‐241, 2004.
 391.Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6: 772‐783, 2006.
 392.Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer 2: 862‐871, 2002.
 393.Tisdale MJ. Molecular pathways leading to cancer cachexia. Physiology (Bethesda) 20: 340‐348, 2005.
 394.Tisdale MJ. Cancer cachexia. Curr Opin Gastroenterol 26: 146‐151, 2010.
 395.Topalian SL, Drake CG, Pardoll DM. Targeting the PD‐1/B7‐H1(PD‐L1) pathway to activate anti‐tumor immunity. Curr Opin Immunol 24: 207‐212, 2012.
 396.Toren P, Venkateswaran V. Periprostatic adipose tissue and prostate cancer progression: New insights into the tumor microenvironment. Clin Genitourin Cancer 12: 21‐26, 2014.
 397.Travers RL, Motta AC, Betts JA, Bouloumié A, Thompson D. The impact of adiposity on adipose tissue‐resident lymphocyte activation in humans. Int J Obes (Lond) 39: 762‐769, 2015.
 398.Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 93: 1‐21, 2013.
 399.Trojan L, Michel MS, Rensch F, Jackson DG, Alken P, Grobholz R. Lymph and blood vessel architecture in benign and malignant prostatic tissue: Lack of lymphangiogenesis in prostate carcinoma assessed with novel lymphatic marker lymphatic vessel endothelial hyaluronan receptor (LYVE‐1). J Urol 172: 103‐107, 2004.
 400.Trottier MD, Naaz A, Li Y, Fraker PJ. Enhancement of hematopoiesis and lymphopoiesis in diet‐induced obese mice. Proc Natl Acad Sci U S A 109: 7622‐7629, 2012.
 401.Trujillo KA, Heaphy CM, Mai M, Vargas KM, Jones AC, Vo P, Butler KS, Joste NE, Bisoffi M, Griffith JK. Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 129: 1310‐1321, 2011.
 402.Trujillo ME, Scherer PE. Adipose tissue‐derived factors: impact on health and disease. Endocr Rev 27: 762‐778, 2006.
 403.Tsekouras A, Mantas D, Tsilimigras DI, Ntanasis‐Stathopoulos I, Kontos M, Zografos GC. Adipose‐derived stem cells for breast reconstruction after breast surgery–‐preliminary results. Case Reports Plast Surg Hand Surg 4: 35‐41, 2017.
 404.Tuck AB, Park M, Sterns EE, Boag A, Elliott BE. Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol 148: 225‐232, 1996.
 405.Turkoz FP, Solak M, Petekkaya I, Keskin O, Kertmen N, Sarici F, Arik Z, Babacan T, Ozisik Y, Altundag K. The prognostic impact of obesity on molecular subtypes of breast cancer in premenopausal women. J BUON 18: 335‐341, 2013.
 406.Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR. Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res 8: 2912‐2923, 2002.
 407.Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F. Proteomics. Tissue‐based map of the human proteome. Science 347: 1260419, 2015.
 408.Ursin G, Hovanessian‐Larsen L, Parisky YR, Pike MC, Wu AH. Greatly increased occurrence of breast cancers in areas of mammographically dense tissue. Breast Cancer Res 7: R605‐R608, 2005.
 409.Vainio H, Kaaks R, Bianchini F. Weight control and physical activity in cancer prevention: International evaluation of the evidence. Eur J Cancer Prev 11(Suppl 2): S94‐S100, 2002.
 410.Valastyan S, Weinberg RA. Tumor metastasis: Molecular insights and evolving paradigms. Cell 147: 275‐292, 2011.
 411.Valor L, Teijeiro R, Aristimuno C, Faure F, Alonso B, de Andres C, Tejera M, Lopez‐Lazareno N, Fernandez‐Cruz E, Sanchez‐Ramon S. Estradiol‐dependent perforin expression by human regulatory T‐cells. Eur J Clin Invest 41: 357‐364, 2011.
 412.van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 18: 2569‐2578, 2009.
 413.van Roermund JG, Hinnen KA, Tolman CJ, Bol GH, Witjes JA, Bosch JL, Kiemeney LA, van Vulpen M. Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients. BJU Int 107: 1775‐1779, 2011.
 414.van Roermund JGH, Bol GH, Alfred Witjes J, Ruud Bosch JLH, Kiemeney LA, van Vulpen M. Periprostatic fat measured on computed tomography as a marker for prostate cancer aggressiveness. World J Urol 28: 699‐704, 2010.
 415.van Spriel AB, Leusen JHW, van Egmond M, Dijkman HBPM, Assmann KJM, Mayadas TN, van de Winkel JGJ. Mac‐1 (CD11b/CD18) is essential for Fc receptor–mediated neutrophil cytotoxicity and immunologic synapse formation. Blood 97: 2478‐2486, 2001.
 416.Vandeweyer E, Hertens D. Quantification of glands and fat in breast tissue: An experimental determination. Ann Anat 184: 181‐184, 2002.
 417.Venkatasubramanian PN, Brendler CB, Plunkett BA, Crawford SE, Fitchev PS, Morgan G, Cornwell ML, McGuire MS, Wyrwicz AM, Doll JA. Periprostatic adipose tissue from obese prostate cancer patients promotes tumor and endothelial cell proliferation: a functional and MR imaging pilot study. Prostate 74: 326‐335, 2014.
 418.Vleugel MM, Bos R, van der Groep P, Greijer AE, Shvarts A, Stel HV, van der Wall E, van Diest PJ. Lack of lymphangiogenesis during breast carcinogenesis. J Clin Pathol 57: 746‐751, 2004.
 419.Vogel WF. Collagen‐receptor signaling in health and disease. Eur J Dermatol 11: 506‐514, 2001.
 420.von Drygalski A, Tran TB, Messer K, Pu M, Corringham S, Nelson C, Ball ED. Obesity is an independent predictor of poor survival in metastatic breast cancer: Retrospective analysis of a patient cohort whose treatment included high‐dose chemotherapy and autologous stem cell support. Int J Breast Cancer 2011: 523276, 2011.
 421.Vona‐Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14: 189‐206, 2007.
 422.Wagner M, Bjerkvig R, Wiig H, Melero‐Martin JM, Lin RZ, Klagsbrun M, Dudley AC. Inflamed tumor‐associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis. Angiogenesis 15: 481‐495, 2012.
 423.Wagner M, Dudley AC. A three‐party alliance in solid tumors: Adipocytes, macrophages and vascular endothelial cells. Adipocyte 2: 67‐73, 2013.
 424.Walz J, Burnett AL, Costello AJ, Eastham JA, Graefen M, Guillonneau B, Menon M, Montorsi F, Myers RP, Rocco B, Villers A. A critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. Eur Urol 57: 179‐192, 2010.
 425.Wang L, Pino‐Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A 105: 9331‐9336, 2008.
 426.Wang YY, Attane C, Milhas D, Dirat B, Dauvillier S, Guerard A, Gilhodes J, Lazar I, Alet N, Laurent V, Le Gonidec S, Biard D, Herve C, Bost F, Ren GS, Bono F, Escourrou G, Prentki M, Nieto L, Valet P, Muller C. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2: e87489, 2017.
 427.Wang YY, Lehuede C, Laurent V, Dirat B, Dauvillier S, Bochet L, Le Gonidec S, Escourrou G, Valet P, Muller C. Adipose tissue and breast epithelial cells: A dangerous dynamic duo in breast cancer. Cancer Lett 324: 142‐151, 2012.
 428.Ward BR, Arslanian SA, Andreatta E, Schwartz LB. Obesity is not linked with increased whole‐body mast cell burden in children. J Allergy Clin Immunol 129: 1164‐1166.e1164, 2012.
 429.Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796‐1808, 2003.
 430.Weitman ES, Aschen SZ, Farias‐Eisner G, Albano N, Cuzzone DA, Ghanta S, Zampell JC, Thorek D, Mehrara BJ. Obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes. PLoS One 8: e70703, 2013.
 431.Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M, Pucci F, Di Serio C, Naldini L, De Palma M, Tozer GM. TIE2‐expressing macrophages limit the therapeutic efficacy of the vascular‐disrupting agent combretastatin A4 phosphate in mice. J Clin Invest 121: 1969, 2011.
 432.Weng N. Aging of the immune system: How much can the adaptive immune system adapt? Immunity 24: 495‐499, 2006.
 433.Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O'Brien PE, Harrison LC. Pro‐inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59: 1648‐1656, 2010.
 434.Werno C, Menrad H, Weigert A, Dehne N, Goerdt S, Schledzewski K, Kzhyshkowska J, Brune B. Knockout of HIF‐1alpha in tumor‐associated macrophages enhances M2 polarization and attenuates their pro‐angiogenic responses. Carcinogenesis 31: 1863‐1872, 2010.
 435.Whiteside TL. The role of immune cells in the tumor microenvironment. Cancer Treat Res 130: 103‐124, 2006.
 436.Widschwendter P, Friedl TW, Schwentner L, DeGregorio N, Jaeger B, Schramm A, Bekes I, Deniz M, Lato K, Weissenbacher T, Kost B, Andergassen U, Jueckstock J, Neugebauer J, Trapp E, Fasching PA, Beckmann MW, Schneeweiss A, Schrader I, Rack B, Janni W, Scholz C. The influence of obesity on survival in early, high‐risk breast cancer: Results from the randomized SUCCESS A trial. Breast Cancer Res 17: 129, 2015.
 437.Wilke CM, Wu K, Zhao E, Wang G, Zou W. Prognostic significance of regulatory T cells in tumor. Int J Cancer 127: 748‐758, 2010.
 438.Williams CB, Yeh ES, Soloff AC. Tumor‐associated macrophages: Unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer 2: 2016.
 439.Williams CS, Leek RD, Robson AM, Banerji S, Prevo R, Harris AL, Jackson DG. Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer. J Pathol 200: 195‐206, 2003.
 440.Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO. Tumor‐secreted vascular endothelial growth factor‐C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res 65: 9789‐9798, 2005.
 441.Woo S, Cho JY, Kim SY, Kim SH. Periprostatic fat thickness on MRI: Correlation with Gleason score in prostate cancer. AJR Am J Roentgenol 204: W43‐W47, 2015.
 442.Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ. ROCK‐generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three‐dimensional collagen matrix. J Cell Biol 163: 583‐595, 2003.
 443.Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford, England) 49: 1618‐1631, 2010.
 444.Wu D, Molofsky AB, Liang HE, Ricardo‐Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332: 243‐247, 2011.
 445.Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150: 366‐376, 2012.
 446.Wynn TA, Barron L. Macrophages: Master regulators of inflammation and fibrosis. Semin Liver Dis 30: 245‐257, 2010.
 447.Xia S, Sha H, Yang L, Ji Y, Ostrand‐Rosenberg S, Qi L. Gr‐1+ CD11b+ myeloid‐derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J Biol Chem 286: 23591‐23599, 2011.
 448.Xiang M, Gu Y, Zhao F, Lu H, Chen S, Yin L. Mast cell tryptase promotes breast cancer migration and invasion. Oncol Rep 23: 615‐619, 2010.
 449.Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity‐related insulin resistance. J Clin Invest 112: 1821‐1830, 2003.
 450.Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW. Obesity activates a program of lysosomal‐dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 18: 816‐830, 2013.
 451.Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino‐Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL. Transcriptome‐based network analysis reveals a spectrum model of human macrophage activation. Immunity 40: 274‐288, 2014.
 452.Yaffe MJ. Mammographic density. Measurement of mammographic density. Breast Cancer Res 10: 209, 2008.
 453.Yaghjyan L, Colditz GA, Collins LC, Schnitt SJ, Rosner B, Vachon C, Tamimi RM. Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to tumor characteristics. J Natl Cancer Inst 103: 1179‐1189, 2011.
 454.Yamaguchi J, Ohtani H, Nakamura K, Shimokawa I, Kanematsu T. Prognostic impact of marginal adipose tissue invasion in ductal carcinoma of the breast. Am J Clin Pathol 130: 382‐388, 2008.
 455.Yang H, Youm YH, Vandanmagsar B, Ravussin A, Gimble JM, Greenway F, Stephens JM, Mynatt RL, Dixit VD. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: Implications for systemic inflammation and insulin resistance. J Immunol 185: 1836‐1845, 2010.
 456.Yang H, Youm YH, Vandanmagsar B, Rood J, Kumar KG, Butler AA, Dixit VD. Obesity accelerates thymic aging. Blood 114: 3803‐3812, 2009.
 457.Yang S, Zhang Q, Liu S, Wang AR, You Z. PD‐1, PD‐L1 and PD‐L2 expression in mouse prostate cancer. Am J Clin Exp Urol 4: 1‐8, 2016.
 458.Yeh HC, Platz EA, Wang NY, Visvanathan K, Helzlsouer KJ, Brancati FL. A prospective study of the associations between treated diabetes and cancer outcomes. Diabetes Care 35: 113‐118, 2012.
 459.Yoshida S, Hamuy R, Hamada Y, Yoshimoto H, Hirano A, Akita S. Adipose‐derived stem cell transplantation for therapeutic lymphangiogenesis in a mouse secondary lymphedema model. Regen Med 10: 549‐562, 2015.
 460.Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Gyori G, Zlabinger GJ, Stulnig TM. Human adipose tissue macrophages are of an anti‐inflammatory phenotype but capable of excessive pro‐inflammatory mediator production. Int J Obes (Lond) 31: 1420‐1428, 2007.
 461.Zeyda M, Huber J, Prager G, Stulnig TM. Inflammation correlates with markers of T‐cell subsets including regulatory T cells in adipose tissue from obese patients. Obesity (Silver Spring) 19: 743‐748, 2011.
 462.Zhang T, Tseng C, Zhang Y, Sirin O, Corn PG, Li‐Ning‐Tapia EM, Troncoso P, Davis J, Pettaway C, Ward J, Frazier ML, Logothetis C, Kolonin MG. CXCL1 mediates obesity‐associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat Commun 7: 11674, 2016.
 463.Zhang X, Zhou G, Sun B, Zhao G, Liu D, Sun J, Liu C, Guo H. Impact of obesity upon prostate cancer‐associated mortality: A meta‐analysis of 17 cohort studies. Oncol Lett 9: 1307‐1312, 2015.
 464.Zhang Y, Daquinag AC, Amaya‐Manzanares F, Sirin O, Tseng C, Kolonin MG. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res 72: 5198‐5208, 2012.
 465.Zhou Y, Yu X, Chen H, Sjoberg S, Roux J, Zhang L, Ivoulsou AH, Bensaid F, Liu CL, Liu J, Tordjman J, Clement K, Lee CH, Hotamisligil GS, Libby P, Shi GP. Leptin deficiency shifts mast cells toward anti‐inflammatory actions and protects mice from obesity and diabetes by polarizing M2 macrophages. Cell Metab 22: 1045‐1058, 2015.
 466.Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6: 295‐307, 2006.
 467.Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13: 4279‐4295, 2002.
 468.Zumsteg A, Baeriswyl V, Imaizumi N, Schwendener R, Ruegg C, Christofori G. Myeloid cells contribute to tumor lymphangiogenesis. PLoS One 4: e7067, 2009.

 

Teaching Material

A. J. Cozzo, A. M. Fuller, L. Makowski. Contribution of Adipose Tissue to Development of Cancer. Compr Physiol. 8: 2018, 237-282.

Didactic Synopsis

Major Teaching Points:

  1. Solid tumor growth requires the interaction of tumor cells with the surrounding tissue, leading to a view of tumors as communities rather than exclusively tumor cells.
  2. Adipose tissue, or fat, plays important roles in cancer risk and outcome because many tumors grow close to or in direct contact with adipose.
  3. The adipose community—or microenvironment—includes adipocytes and adipose-associated stromal and vascular components, such as fibroblasts and other connective tissue cells, stem cells, endothelial cells, innate and adaptive immune cells, and extracellular signaling and matrix components.
  4. Herein, we review the cellular and noncellular parts of the adipose “organ” and the mechanisms by which varied microenvironmental components contribute to tumor development, with emphasis on obesity.
  5. Obesity dramatically modifies the adipose tissue microenvironment in numerous ways, which intriguingly resemble shifts observed within the tumor microenvironment.
  6. Understanding neighboring adipose is critical in tumorigenesis.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Tumors as communities.

Teaching point(s):

  • Tumor cells grow in the context of immune cells, stromal cells, and noncellular extracellular matrix.
  • Adjacent adipose (fat) tissue may influence tumor growth.

Figure 2. The adipose organ is comprised of several distinct adipose depots.

This figure illustrates that there are different types of adipose depots in humans and mice with many conserved similarities between species.

Figure 3. Approximate composition of human white adipose tissue stromal-vascular fraction (percent cellularity).

This figure illustrates the proportions of the primary cells in human adipose tissue with immune cells being the most represented.

Figure 4. Rising global and US obesity rates.

Teaching point(s):

  • Obesity has increased globally over 4 decades with women having higher prevalence of obesity than men.
  • Morbid or class III obesity is highly prevalent in the US compared to globally, with higher prevalence in women compared to men.
  • Non-Hispanic black women have the greatest prevalence of obesity.

Figure 5. Comparison of mouse and human mammary gland anatomical structure.

Teaching point(s):

  • The mouse mammary gland elongates and branches at Terminal End Buds (TEBs).
  • The human mammary gland ends in the functional terminal ductal lobular unit (TDLU).

Figure 6: Comparison of mouse and human mammary gland histology.

This figure illustrates similarities and differences between mouse mammary fat pad and normal human breast. The human breast has greater stromal content and fewer adipocytes.

Figure 7. Adipose-breast cancer interactions in mice and humans.

This figure illustrates how tumors can grow near or invade into adjacent adipose tissue.

Figure 8. Anatomical comparison of mouse (left) and human (right) prostate glands.

This figure illustrates that the prostate surrounds the bladder in both humans and mice, yet the lobes, or zones, are anatomically different between species.

Figure 9. Desmoplasia and cancer-associated adipocytes.

Teaching points:

  • In tumors, chronic activation of the wound-repair response results in desmoplasia, or excess collagenous extracellular matrix production, within tumors. Asterisks (*) indicate desmoplastic stroma.
  • Cancer-associated adipocytes (black arrows) at or near the tumor invasive front become smaller and exhibit decreased expression of adipocyte markers, while the number of fibroblast-like cells increases.

Figure 10. Obesity-associated modifications in the adipose tissue microenvironment.

Teaching points:

  • Adipose tissue expansion in obesity occurs in association with extracellular matrix changes such as fibrosis.
  • Adipocyte hypertrophy and hypoxia trigger macrophage infiltration and crown-like structure formation.
  • Fibrosis and inflammation characterize obese adipose tissue.

Figure 11. HGF/cMET: an oncogenic signaling cascade.

Teaching points:

  • Growth factors such as hepatocyte growth factor (HGF) are secreted by stromal cells such as fibroblasts, adipocytes, and macrophages.
  • HGF initiates a growth program in epithelial cells leading to cancer and metastasis.

Figure 12. Adipocyte subtypes and secreted factors.

Teaching points:

  • There are several types of adipocytes.
  • White adipocytes contain a large, unilocular lipid droplet and are specialized for storage of neutral lipids.
  • Brown and/or beige adipocytes have increased mitochondrial content relative to white adipocytes and play important roles in thermogenesis.
  • “Pink” adipocytes have been described in murine mammary gland, arising exclusively during pregnancy and lactation.
  • Depending on depot and metabolic state, adipocytes secrete a broad range of signaling molecules.

Figure 13. Adipocytes promote tumor progression and metastasis.

Teaching points:

  • Adipocytes within the tumor mass are termed cancer-associated adipocytes (also referred to as peritumoral, intratumoral, or tumor-infiltrating adipocytes.
  • Cancer associated adipocytes secrete proteins, metabolites, and exosomes that can alter cancer cell biology.
  • Cancer associated adipocytes also secrete a variety of factors that promote tumor growth, epithelial-mesenchymal transition (EMT), acquisition of stem-like features, invasive behavior, and metastasis.

Figure 14. Obesity, cancer increase circulating adipose stromal cells (ASCs).

This cartoon illustrates that ASCs are multipotent stem cells that increase with obesity and traffic to tumors to increase tumor growth and angiogenesis.

Figure 15. Hypoxia and the angiogenic switch.

Teaching points:

  • Commonalities between expanding adipose and a growing tumor exist, and include the necessity for increased vascularization and production of proangiogenic factors.
  • Hypoxia develops and triggers release of many growth factors and other cytokines that enable blood vessel growth, a process known as the “angiogenic switch.”
  • Increased vascularization alleviates regional hypoxia and facilitates further tissue expansion of the adipose depot or tumor.

Figure 16. Mammary HGF/cMET signaling in the in C3(1)-Tag mouse model of basal-like breast cancer.

Teaching points:

  • Obesity increased HGF production by stromal cells, promoting tumor growth and angiogenesis.
  • HGF/cMET-mediated tumor promotion was reversible by weight loss or cMET inhibition.

Figure 17. Summary of changes in immune cell profile during progression to obesity.

Teaching points:

  • Changes in immune cell populations from days to weeks to months after obesogenic high fat diet exposure are shown.
  • Immunoregulatory cells such as tissue-resident macrophages, regulatory T cells, and eosinophils are present in the lean state at the start of the timeline but prevalence declines with obesity.
  • Within days of exposure to an obesogenic diet neutrophils infiltrate adipose.
  • Over weeks to months, an increase in CD8 + T cells, macrophages, and myeloid-derived suppressor cells (MDSCs) results in a mix of pro- and anti-inflammatory cells.
  • In prolonged obesity, adipose mast cell content may also increase.

Figure 18. Macrophage activation as a spectrum.

Teaching points:

  • Tissue macrophages have multiple sources. Some macrophages seed tissues during fetal development and self-maintain through proliferation, while others infiltrate tissue as monocyte-derived macrophages.
  • Unstimulated macrophages can be stimulated in vitro to generate M1 macrophages (right) or M2 macrophages (left) using single cytokines or cocktails of cytokines plus other stimuli.
  • However, tissue macrophages in vivo lie along a spectrum and are exquisitely plastic, often expressing one or more markers of both “M1” and “M2” subtypes.
  • Macrophage functions and phenotypes in tissues vary by tissue type and timing of residence.

Fig. 19. Adipose tissue macrophage ontogeny.

Teaching points:

  • Tissue-resident macrophages (e.g., Kupffer cells, microglia) are derived from embryonic sites including the yolk sac and fetal liver.
  • The relative contribution of yolk sac, fetal liver, and bone marrow-derived macrophages within adipose tissue depots has not been established.
  • It is established that inflammatory, bone-marrow-derived macrophages increase in obese adipose.

Figure 20. Tumor-Associated Neutrophils have N1 and N2-like phenotypes.

Teaching points:

  • This cartoon illustrates that like macrophages, there are varied neutrophil phenotypes that are considered both pro- and antitumoral.
  • N1 neutrophils support cytotoxic CD8 + T cell activity that would limit tumor progression.
  • N2 neutrophils secrete many angiogenic and immunosuppressive mediators to support tumor growth.
  • ROS secreted by both N1 and N2 may both promote genotoxicity in tumor initiation, or in contrast, can be cytotoxic to growing tumors.
  • Neutrophil production of reactive oxygen species, for example, through myeloperoxidase (MPO) expression, contributes to oxidative stress and fibrotic changes.

Figure 21. Mast cells: Unappreciated players in adipose and tumor biology.

Teaching points:

  • Mast cell content and activation (degranulation) increases with obesity in adipose tissue.
  • Mast cells contribute to tumor progression through factors that drive growth and angiogenesis, or cause immunosuppression to facilitate tumor immune evasion. However, some mast cell-derived factors also limit tumor growth.

 


Related Articles:

Adipose Tissue‐Derived Plasminogen Activator Inhibitor‐1 Function and Regulation
Contribution of Maladaptive Adipose Tissue Expansion to Development of Cardiovascular Disease
The Microcirculation in Inflammation

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Alyssa J. Cozzo, Ashley M. Fuller, Liza Makowski. Contribution of Adipose Tissue to Development of Cancer. Compr Physiol 2017, 8: 237-282. doi: 10.1002/cphy.c170008