Adipocytes in the Tumour Microenvironment

  • Nikitha K. Pallegar
  • Sherri L. ChristianEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1234)


Adipose tissue contribution to body mass ranges from 6% in male athletes to over 25% in obese men and over 30% in obese women. Crosstalk between adipocytes and cancer cells that exist in close proximity can lead to changes in the function and phenotype of both cell types. These interactions actively alter the tumour microenvironment (TME). Obesity is one of the major risk factors for multiple types of cancer, including breast cancer. In obesity, the increase in both size and number of adipocytes leads to instability of the TME, as well as increased hypoxia within the TME, which further enhances tumour invasion and metastasis. In this chapter, we will discuss the diverse aspects of adipocytes and adipocyte-derived factors that affect the TME as well as tumour progression and metastasis. In addition, we discuss how obesity affects the TME. We focus primarily on breast cancer but discuss what is known in other cancer types when relevant. We finish by discussing the studies needed to further understand these complex interactions.


Tumour microenvironment Adipocytes Obesity Paracrine/autocrine signaling Adipokines Lipid metabolites Breast cancer Metastasis Epithelial to mesenchymal transition Mesenchymal-to-epithelial transition Extracellular matrix (ECM) Hypoxia Chronic inflammation ECM remodeling 


  1. 1.
    Place AE, Jin Huh S, Polyak K (2011) The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res 13:227. Scholar
  2. 2.
    Sundaram S, Johnson AR, Makowski L (2013) Obesity, metabolism and the microenvironment: links to cancer. J Carcinog 12:19. Scholar
  3. 3.
    Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331:1559–1564. Scholar
  4. 4.
    Wu Y, Sarkissyan M, Vadgama J (2016) Epithelial-mesenchymal transition and breast cancer. J Clin Med 5:13. Scholar
  5. 5.
    Lee Y, Jung WH, Koo JS (2015) Adipocytes can induce epithelial-mesenchymal transition in breast cancer cells. Breast Cancer Res Treat 153:323–335. Scholar
  6. 6.
    Ritter A, Friemel A, Fornoff F et al (2015) Characterization of adipose-derived stem cells from subcutaneous and visceral adipose tissues and their function in breast cancer cells. Oncotarget 6:34475–34493. Scholar
  7. 7.
    Ogunwobi OO, Liu C (2011) Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways. Clin Exp Metastasis 28:721–731. Scholar
  8. 8.
    Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19:156–172. Scholar
  9. 9.
    Moreno-Bueno G, Portillo F, Cano A (2008) Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27:6958–6969. Scholar
  10. 10.
    Thiery JP, Lim CT (2013) Tumor dissemination: an EMT affair. Cancer Cell 23:272–273. Scholar
  11. 11.
    Battula VL, Evans KW, Hollier BG et al (2010) Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells 28:1435–1445. Scholar
  12. 12.
    Mani SA, Guo W, Liao M-JJ et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715. Scholar
  13. 13.
    Ota I, Li X-Y, Hu Y, Weiss SJ (2009) Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci 106:20318–20323. Scholar
  14. 14.
    Chavey C, Mari B, Monthouel M-N et al (2003) Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 278:11888–11896. Scholar
  15. 15.
    Tsai JH, Yang J (2013) Epithelial – mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:2192–2206. Scholar
  16. 16.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428CrossRefGoogle Scholar
  17. 17.
    Drake JM, Strohbehn G, Bair TB et al (2009) ZEB1 enhances transendothelial migration and represses the epithelial phenotype of prostate cancer cells. Mol Biol Cell 20:2207–2217. Scholar
  18. 18.
    Gupta GP, Nguyen DX, Chiang AC et al (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446:765–770. Scholar
  19. 19.
    Yu M, Bardia A, Wittner BS et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580–584. Scholar
  20. 20.
    Hüsemann Y, Geigl JB, Schubert F et al (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13:58–68. Scholar
  21. 21.
    Yao D, Dai C, Peng S (2011) Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res 9:1608–1620. Scholar
  22. 22.
    Xie H, Liao N, Lan F et al (2017) 3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition. Int J Mol Med 41:1385–1396. Scholar
  23. 23.
    Jie X-X, Zhang X-Y, Xu C-J et al (2017) Epithelial-to-mesenchymal transition, circulating tumor cells and cancer metastasis: mechanisms and clinical applications. Oncotarget 8:81558–81571. Scholar
  24. 24.
    Zhou XD, Agazie YM (2008) Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ 15:988–996. Scholar
  25. 25.
    Chao YL, Shepard CR, Wells A (2010) Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 9:179. Scholar
  26. 26.
    Tsuji T, Ibaragi S, Hu GF (2009) Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res 69:7135–7139CrossRefGoogle Scholar
  27. 27.
    Wells A, Yates C, Shepard CR (2008) E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 25:621–628. Scholar
  28. 28.
    Guaita-Esteruelas S, Gumà J, Masana L, Borràs J (2018) The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5. Mol Cell Endocrinol 462:107–118. Scholar
  29. 29.
    Vandeweyer E, Hertens D (2002) Quantification of glands and fat in breast tissue: an experimental determination. Ann Anat 184:181–184. Scholar
  30. 30.
    Duong MN, Geneste A, Fallone F et al (2017) The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance. Oncotarget 8:57622–57641. Scholar
  31. 31.
    Nieman KM, Romero IL, Van Houten B, Lengyel E (2013) Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta Mol Cell Biol Lipids 1831:1533–1541. Scholar
  32. 32.
    Divella R, De Luca R, Abbate I et al (2016) Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation. J Cancer 7:2346–2359. Scholar
  33. 33.
    Ribeiro RJT, Monteiro CPD, Cunha VFPM et al (2012) Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile. Cell Physiol Biochem 29:233–240. Scholar
  34. 34.
    Nieman KM, Kenny HA, Penicka CV et al (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503. Scholar
  35. 35.
    Abramczyk H, Surmacki J, Kopeć M et al (2015) The role of lipid droplets and adipocytes in cancer. Raman imaging of cell cultures: MCF10A, MCF7, and MDA-MB-231 compared to adipocytes in cancerous human breast tissue. Analyst 140:2224–2235. Scholar
  36. 36.
    Zoico E, Darra E, Rizzatti V et al (2018) Role of adipose tissue in melanoma cancer microenvironment and progression. Int J Obes 42:344–352. Scholar
  37. 37.
    Berry DC, Stenesen D, Zeve D, Graff JM (2013) The developmental origins of adipose tissue. Development 140:3939–3949CrossRefGoogle Scholar
  38. 38.
    Peinado JR, Pardo M, de la Rosa O, Malagón MM (2012) Proteomic characterization of adipose tissue constituents, a necessary step for understanding adipose tissue complexity. Proteomics 12:607–620. Scholar
  39. 39.
    Morton GJ, Cummings DE, Baskin DG et al (2006) Central nervous system control of food intake and body weight. Nature 443:289–295. Scholar
  40. 40.
    Guyenet SJ, Schwartz MW (2012) Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab 97:745–755. Scholar
  41. 41.
    Iikuni N, Lam QLK, Lu L et al (2008) Leptin and inflammation. Curr Immunol Rev 4:70–79. Scholar
  42. 42.
    Ray A, Nkhata KJ, Cleary MP (2007) Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. Int J Oncol 30:1499–1509PubMedGoogle Scholar
  43. 43.
    Jardé T, Caldefie-Chézet F, Damez M et al (2008) Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol Rep 19:905–911PubMedGoogle Scholar
  44. 44.
    Mullen M, Gonzalez-Perez RR (2016) Leptin-induced JAK/STAT signaling and cancer growth. Vaccine 4:26. Scholar
  45. 45.
    Nepal S, Kim MJ, Hong JT et al (2015) Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: involvement of p53/FoxO3A axis. Oncotarget 6:7166–7181. Scholar
  46. 46.
    Zheng Q, Banaszak L, Fracci S et al (2013) Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells. Endocr Relat Cancer 20:797–808. Scholar
  47. 47.
    Stern JH, Rutkowski JM, Scherer PE (2016) Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 23:770–784. Scholar
  48. 48.
    Kwon H, Pessin JE (2013) Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne) 4:71. Scholar
  49. 49.
    Shehzad A, Iqbal W, Shehzad O, Lee YS (2012) Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens) 11:8–20CrossRefGoogle Scholar
  50. 50.
    Kimlin LC, Casagrande G, Virador VM (2013) In vitro three-dimensional (3D) models in cancer research: an update. Mol Carcinog 52:167–182. Scholar
  51. 51.
    Sultana R, Kataki AC, Borthakur BB et al (2017) Imbalance in leptin-adiponectin levels and leptin receptor expression as chief contributors to triple negative breast cancer progression in Northeast India. Gene 621:51–58. Scholar
  52. 52.
    Gyamfi J, Eom M, Koo J-S, Choi J (2018) Multifaceted roles of Interleukin-6 in adipocyte–breast cancer cell interaction. Transl Oncol 11:275–285. Scholar
  53. 53.
    Esquivel-Velázquez M, Ostoa-Saloma P, Palacios-Arreola MI et al (2015) The role of cytokines in breast cancer development and progression. J Interf Cytokine Res 35:1–16. Scholar
  54. 54.
    Iyengar NM, Gucalp A, Dannenberg AJ, Hudis CA (2016) Obesity and cancer mechanisms: tumor microenvironment and inflammation. J Clin Oncol 34:4270. Scholar
  55. 55.
    Pileczki V, Braicu C, Gherman C, Berindan-Neagoe I (2012) TNF-α gene knockout in triple negative breast cancer cell line induces apoptosis. Int J Mol Sci 14:411–420. Scholar
  56. 56.
    Li J, Han X (2018) Adipocytokines and breast cancer. Curr Probl Cancer 42(2):208–214. Scholar
  57. 57.
    Dusaulcy R, Rancoule C, Grès S et al (2011) Adipose-specific disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid. J Lipid Res 52:1247–1255. Scholar
  58. 58.
    Choi J, Cha YJ, Koo JS (2018) Adipocyte biology in breast cancer: from silent bystander to active facilitator. Prog Lipid Res 69:11–20CrossRefGoogle Scholar
  59. 59.
    Christopoulos PF, Msaouel P, Koutsilieris M et al (2015) The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer 14:43. Scholar
  60. 60.
    Creighton CJ, Casa A, Lazard Z et al (2008) Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast Cancer prognosis. J Clin Oncol 26:4078–4085. Scholar
  61. 61.
    Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928. Scholar
  62. 62.
    Edakuni G, Sasatomi E, Satoh T et al (2001) Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. Pathol Int 51:172–178CrossRefGoogle Scholar
  63. 63.
    Bell LN, Ward JL, Degawa-Yamauchi M et al (2006) Adipose tissue production of hepatocyte growth factor contributes to elevated serum HGF in obesity. Am J Physiol Metab 291:E843–E848. Scholar
  64. 64.
    Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21:297–308. Scholar
  65. 65.
    Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogene 5:e189. Scholar
  66. 66.
    Vander Heiden M, Cantley L, Thompson C (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. Scholar
  67. 67.
    Pavlides S, Whitaker-Menezes D, Castello-Cros R et al (2009) The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001. Scholar
  68. 68.
    Martinez-Outschoorn UE, Pestell RG, Howell A et al (2011) Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells. Cell Cycle 10:4208–4216. Scholar
  69. 69.
    Fadaka A, Ajiboye B, Ojo O et al (2017) Biology of glucose metabolization in cancer cells. J Oncol Sci 3:45–51. Scholar
  70. 70.
    Gupta S, Roy A, Dwarakanath BS (2017) Metabolic cooperation and competition in the tumor microenvironment: implications for therapy. Front Oncol 7:68. Scholar
  71. 71.
    Balaban S, Shearer RF, Lee LS et al (2017) Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab 5:1. Scholar
  72. 72.
    Santos CR, Schulze A (2012) Lipid metabolism in cancer. FEBS J 279:2610–2623. Scholar
  73. 73.
    Fagone P, Jackowski S (2009) Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res 50(Suppl):S311–S316. Scholar
  74. 74.
    Pascual G, Avgustinova A, Mejetta S et al (2017) Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541:41–45. Scholar
  75. 75.
    Lazar I, Clement E, Dauvillier S et al (2016) Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer. Cancer Res 76:4051–4057. Scholar
  76. 76.
    Ojima K, Oe M, Nakajima I et al (2016) Dynamics of protein secretion during adipocyte differentiation. FEBS Open Bio 6(8):816–826CrossRefGoogle Scholar
  77. 77.
    Sun K, Tordjman J, Clément K, Scherer PE (2013) Fibrosis and adipose tissue dysfunction. Cell Metab 18:470–477. Scholar
  78. 78.
    Mariman EC, Wang P (2010) Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci 67:1277–1292CrossRefGoogle Scholar
  79. 79.
    Iyengar P, Espina V, Williams TW et al (2005) 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. Scholar
  80. 80.
    Park J, Scherer PE (2012) Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest 122:4243–4256. Scholar
  81. 81.
    Jia L, Wang S, Cao J et al (2007) siRNA targeted against matrix metalloproteinase 11 inhibits the metastatic capability of murine hepatocarcinoma cell Hca-F to lymph nodes. Int J Biochem Cell Biol 39:2049–2062. Scholar
  82. 82.
    WHO (2016) Obesity and overweight. World Health Organization Fact sheetGoogle Scholar
  83. 83.
    Finkelstein EA, Khavjou OA, Thompson H et al (2012) Obesity and severe obesity forecasts through 2030. Am J Prev Med 42:563–570. Scholar
  84. 84.
    Smith KB, Smith MS (2016) Obesity statistics. Prim Care 43:121–135CrossRefGoogle Scholar
  85. 85.
    Ramos Chaves M, Boléo-Tomé C, Monteiro-Grillo I et al (2010) The diversity of nutritional status in cancer: new insights. Oncologist 15:523–530. Scholar
  86. 86.
    Gioulbasanis I, Martin L, Baracos VE et al (2015) Nutritional assessment in overweight and obese patients with metastatic cancer: does it make sense? Ann Oncol 26:217–221. Scholar
  87. 87.
    Protani M, Coory M, Martin JH (2010) Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 123:627–635. Scholar
  88. 88.
    Chan DS, Norat T (2015) Obesity and breast cancer: not only a risk factor of the disease. Curr Treat Options in Oncol 16:22. Scholar
  89. 89.
    Ewertz M, Jensen M-B, Gunnarsdóttir KÁ et al (2011) Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 29:25–31. Scholar
  90. 90.
    Pierobon M, Frankenfeld CL (2013) Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat 137:307–314. Scholar
  91. 91.
    James FR, Wootton S, Jackson A et al (2015) Obesity in breast cancer--what is the risk factor? Eur J Cancer 51:705–720. Scholar
  92. 92.
    Donohoe CL, Doyle SL, Reynolds JV (2011) Visceral adiposity, insulin resistance and cancer risk. Diabetol Metab Syndr 3:12CrossRefGoogle Scholar
  93. 93.
    Schapira DV, Clark RA, Wolff PA et al (1994) Visceral obesity and breast cancer risk. Cancer 74:632–639.<632::AID-CNCR2820740215>3.0.CO;2-TCrossRefPubMedGoogle Scholar
  94. 94.
    Osman M, Hennessy B (2015) Obesity correlation with metastases development and response to first-line metastatic chemotherapy in breast cancer. Clin Med Insights Oncol 9:105–112. Scholar
  95. 95.
    Tseng LM, Hsui CN, Chen SC et al (2013) Distant metastasis in triple-negative breast cancer. Neoplasma 60:290–294. Scholar
  96. 96.
    Morris EV, Edwards CM (2016) The role of bone marrow adipocytes in bone metastasis. J Bone Oncol 5:121–123. Scholar
  97. 97.
    Chkourko Gusky H, Diedrich J, MacDougald OA, Podgorski I (2016) Omentum and bone marrow: how adipocyte-rich organs create tumour microenvironments conducive for metastatic progression. Obes Rev 17:1015–1029. Scholar
  98. 98.
    Rausch LK, Netzer NC, Hoegel J, Pramsohler S (2017) The linkage between breast cancer, hypoxia, and adipose tissue. Front Oncol 7:211. Scholar
  99. 99.
    Seo BR, Bhardwaj P, Choi S et al (2015) Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 7:301ra130. Scholar
  100. 100.
    Templeton ZS, Lie W-RR, Wang W et al (2015) Breast cancer cell colonization of the human bone marrow adipose tissue niche. Neoplasia 17:849–861. Scholar
  101. 101.
    Maller O, Martinson H, Schedin P (2010) Extracellular Matrix Composition Reveals Complex and Dynamic Stromal-Epithelial Interactions in the Mammary Gland. J Mammary Gland Biol Neoplasia 15:301–18. Scholar
  102. 102.
    Duval K, Grover H, Han L-H et al (2017) Modeling physiological events in 2D vs. 3D cell culture. Physiology (Bethesda) 32:266–277. Scholar
  103. 103.
    Kenny PA, Lee GY, Myers CA et al (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 1:84–96. Scholar
  104. 104.
    Ravi M, Paramesh V, Kaviya SR et al (2015) 3D cell culture systems: advantages and applications. J Cell Physiol 230:16–26. Scholar
  105. 105.
    Baker BM, Chen CS (2012) Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J Cell Sci 125:3015–3024. Scholar
  106. 106.
    Luca AC, Mersch S, Deenen R et al (2013) Impact of the 3D microenvironment on phenotype, gene expression, and EGFR inhibition of colorectal cancer cell lines. PLoS One 8:e59689. Scholar
  107. 107.
    Aljitawi OS, Li D, Xiao Y et al (2014) A novel three-dimensional stromal-based model for in vitro chemotherapy sensitivity testing of leukemia cells. Leuk Lymphoma 55:378–391. Scholar
  108. 108.
    Fang Y, Eglen RM (2017) Three-dimensional cell cultures in drug discovery and development. SLAS Discov 22:456–472. Scholar
  109. 109.
    Pallegar NK, Garland CJ, Mahendralingam M et al (2018) A novel 3-dimensional co-culture method reveals a partial mesenchymal to epithelial transition in breast cancer cells induced by adipocytes. J Mammary Gland Biol Neoplasia 24(1):85–97. Scholar
  110. 110.
    Bidarra SJ, Oliveira P, Rocha S et al (2016) A 3D in vitro model to explore the inter-conversion between epithelial and mesenchymal states during EMT and its reversion. Sci Rep 6:27072. Scholar
  111. 111.
    Seyfried TN, Huysentruyt LC (2013) On the origin of cancer metastasis. Crit Rev Oncog 18:43–73CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of BiochemistryMemorial University of NewfoundlandSt. John’sCanada

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