Skip to main content

Advertisement

Springer Nature Link
Log in

The adipocyte microenvironment and cancer

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ATP:

Adenosine triphosphate

BAT:

Brown adipose tissue

CAA:

Cancer-associated adipocytes

CPT1:

Carnitine palmitoyltransferase 1A

EMT:

Epithelial-mesenchymal transition

FA:

Fatty acids

FABP:

Fatty acid-binding protein

FAT:

Fatty acid translocase

FATP:

Fatty acid transport protein

FAO:

Fatty acid oxidation

Gatm:

Glycine amidinotransferase

HFD:

High-fat diet

MMe:

Metabolically activated macrophages

Mox:

Redox-regulatory macrophages

MAGL:

Monoacylglycerol lipase

miRNA:

MicroRNA

NK:

Natural killer

PDX:

Patient-derived xenograft

PUFA:

Polyunsaturated fatty acids

SAT:

Subcutaneous adipose tissue

SLC27A1:

Solute carrier family 27 member 1

SVF:

Stromal vascular fraction

TAM:

Tumor-associated macrophages

TME:

Tumor microenvironment

Tregs:

T regulatory cells

UCP1:

Uncoupling protein 1

VAT:

Visceral adipose tissue

WAT:

White adipose tissue

References

  1. Lazar, I., Clement, E., Dauvillier, S., Milhas, D., Ducoux-Petit, M., LeGonidec, S., et al. (2016). Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: A novel mechanism linking obesity and cancer. Cancer Research, 76(14), 4051–4057. https://doi.org/10.1158/0008-5472.CAN-16-0651

    Article  CAS  PubMed  Google Scholar 

  2. Nieman, K. M., Romero, I. L., Van Houten, B., & Lengyel, E. (2013). Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochimica et Biophysica Acta, 1831(10), 1533–1541. https://doi.org/10.1016/j.bbalip.2013.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lengyel, E., Makowski, L., DiGiovanni, J., & Kolonin, M. G. (2018). Cancer as a matter of fat: The crosstalk between adipose tissue and tumors. Trends Cancer, 4(5), 374–384. https://doi.org/10.1016/j.trecan.2018.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Duman, C., Yaqubi, K., Hoffmann, A., Acikgoz, A. A., Korshunov, A., Bendszus, M., et al. (2019). Acyl-CoA-binding protein drives glioblastoma tumorigenesis by sustaining fatty acid oxidation. Cell Metabolism, 30(2), 274–289 e275. https://doi.org/10.1016/j.cmet.2019.04.004.

  5. Reilly, S. M., Hung, C. W., Ahmadian, M., Zhao, P., Keinan, O., Gomez, A. V., et al. (2020). Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3. Nature Metabolism, 2(7), 620–634. https://doi.org/10.1038/s42255-020-0217-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Thomas, E. L., Saeed, N., Hajnal, J. V., Brynes, A., Goldstone, A. P., Frost, G., et al. (1998). Magnetic resonance imaging of total body fat. J Appl Physiol (1985), 85(5), 1778–1785. https://doi.org/10.1152/jappl.1998.85.5.1778.

  7. Saito, M., Okamatsu-Ogura, Y., Matsushita, M., Watanabe, K., Yoneshiro, T., Nio-Kobayashi, J., et al. (2009). High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity. Diabetes, 58(7), 1526–1531. https://doi.org/10.2337/db09-0530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kahn, C. R., Wang, G., & Lee, K. Y. (2019). Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. Journal of Clinical Investigation, 129(10), 3990–4000. https://doi.org/10.1172/JCI129187

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vijay, J., Gauthier, M. F., Biswell, R. L., Louiselle, D. A., Johnston, J. J., Cheung, W. A., et al. (2020). Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nature Metabolism, 2(1), 97–109. https://doi.org/10.1038/s42255-019-0152-6

    Article  PubMed  Google Scholar 

  10. Crewe, C., An, Y. A., & Scherer, P. E. (2017). The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis. Journal of Clinical Investigation, 127(1), 74–82. https://doi.org/10.1172/JCI88883

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lauby-Secretan, B., Scoccianti, C., Loomis, D., Grosse, Y., Bianchini, F., Straif, K., et al. (2016). Body fatness and cancer–Viewpoint of the IARC working group. New England Journal of Medicine, 375(8), 794–798. https://doi.org/10.1056/NEJMsr1606602

    Article  PubMed  Google Scholar 

  12. Ringel, A. E., Drijvers, J. M., Baker, G. J., Catozzi, A., Garcia-Canaveras, J. C., Gassaway, B. M., et al. (2020). Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell, 183(7), 1848–1866 e1826. https://doi.org/10.1016/j.cell.2020.11.009.

  13. Maury, E., Ehala-Aleksejev, K., Guiot, Y., Detry, R., Vandenhooft, A., & Brichard, S. M. (2007). Adipokines oversecreted by omental adipose tissue in human obesity. American Journal of Physiology - Endocrinology and Metabolism, 293, E656–E665.

    Article  CAS  Google Scholar 

  14. Dirat, B., Bochet, L., Dabek, M., Daviaud, D., Dauvillier, S., Majed, B., et al. (2011). Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Research, 71(7), 2455–2465. https://doi.org/10.1158/0008-5472.CAN-10-3323

    Article  CAS  PubMed  Google Scholar 

  15. Arner, P., & Kulyte, A. (2015). MicroRNA regulatory networks in human adipose tissue and obesity. Nature Reviews: Endocrinology, 11(5), 276–288. https://doi.org/10.1038/nrendo.2015.25

    Article  CAS  PubMed  Google Scholar 

  16. Maguire, O. A., Ackerman, S. E., Szwed, S. K., Maganti, A. V., Marchildon, F., Huang, X., et al. (2021). Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer. Cell Metabolism, 33(3), 499–512 e496. https://doi.org/10.1016/j.cmet.2021.01.018.

  17. Romero, I. L., McCormick, A., McEwen, K. A., Park, S., Karrison, T., Yamada, S. D., et al. (2012). Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstetrics and Gynecology, 119(1), 61–67. https://doi.org/10.1097/AOG.0b013e3182393ab3

    Article  PubMed  Google Scholar 

  18. Sun, C., Li, X., Guo, E., Li, N., Zhou, B., Lu, H., et al. (2020). MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene, 39(8), 1681–1695. https://doi.org/10.1038/s41388-019-1090-1

    Article  CAS  PubMed  Google Scholar 

  19. Goodwin, P. J., Chen, B. E., Gelmon, K. A., Whelan, T. J., Ennis, M., Lemieux, J., et al. (2022). Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: The MA.32 randomized clinical trial. JAMA, 327(20), 1963–1973. https://doi.org/10.1001/jama.2022.6147.

  20. Kazantzis, M., & Stahl, A. (2012). Fatty acid transport proteins, implications in physiology and disease. Biochimica et Biophysica Acta, 1821(5), 852–857. https://doi.org/10.1016/j.bbalip.2011.09.010

    Article  CAS  PubMed  Google Scholar 

  21. Nath, A., Li, I., Roberts, L. R., & Chan, C. (2015). Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Scientific Reports, 5, 14752. https://doi.org/10.1038/srep14752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nath, A., & Chan, C. (2016). Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Scientific Reports, 6, 18669. https://doi.org/10.1038/srep18669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hao, Y., Li, D., Xu, Y., Ouyang, J., Wang, Y., Zhang, Y., et al. (2019). Investigation of lipid metabolism dysregulation and the effects on immune microenvironments in pan-cancer using multiple omics data. BMC Bioinformatics, 20(Suppl 7), 195. https://doi.org/10.1186/s12859-019-2734-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ladanyi, A., Mukherjee, A., Kenny, H. A., Johnson, A., Mitra, A. K., Sundaresan, S., et al. (2018). Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene, 37(17), 2285–2301. https://doi.org/10.1038/s41388-017-0093-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pascual, G., Avgustinova, A., Mejetta, S., Martin, M., Castellanos, A., Attolini, C. S., et al. (2017). Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature, 541(7635), 41–45. https://doi.org/10.1038/nature20791

    Article  CAS  PubMed  Google Scholar 

  26. Pascual, G., Dominguez, D., Elosua-Bayes, M., Beckedorff, F., Laudanna, C., Bigas, C., et al. (2021). Dietary palmitic acid promotes a prometastatic memory via Schwann cells. Nature, 599(7885), 485–490. https://doi.org/10.1038/s41586-021-04075-0

    Article  CAS  PubMed  Google Scholar 

  27. Choi, C. H., Choi, J. J., Park, Y. A., Lee, Y. Y., Song, S. Y., Sung, C. O., et al. (2012). Identification of differentially expressed genes according to chemosensitivity in advanced ovarian serous adenocarcinomas: Expression of GRIA2 predicts better survival. British Journal of Cancer, 107(1), 91–99. https://doi.org/10.1038/bjc.2012.217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Watt, M. J., Clark, A. K., Selth, L. A., Haynes, V. R., Lister, N., Rebello, R., et al. (2019). Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Science Translational Medicine, 11(478). https://doi.org/10.1126/scitranslmed.aau5758.

  29. Zhang, M., Di Martino, J. S., Bowman, R. L., Campbell, N. R., Baksh, S. C., Simon-Vermot, T., et al. (2018). Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discovery, 8(8), 1006–1025. https://doi.org/10.1158/2159-8290.CD-17-1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nomura, D. K., Long, J. Z., Niessen, S., Hoover, H. S., Ng, S. W., & Cravatt, B. F. (2010). Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell, 140, 49–61.

    Article  CAS  Google Scholar 

  31. Nieman, K. M., Kenny, H. A., Penicka, C. V., Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M. R., et al. (2011). Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine, 17(11), 1498–1503. https://doi.org/10.1038/nm.2492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Eckert, M. A., Coscia, F., Chryplewicz, A., Chang, J. W., Hernandez, K. M., Pan, S., et al. (2019). Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature, 569(7758), 723–728. https://doi.org/10.1038/s41586-019-1173-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mukherjee, A., Chiang, C. Y., Daifotis, H. A., Nieman, K. M., Fahrmann, J. F., Lastra, R. R., et al. (2020). Adipocyte-induced FABP4 expression in ovarian cancer cells promotes metastasis and mediates carboplatin resistance. Cancer Research, 80(8), 1748–1761. https://doi.org/10.1158/0008-5472.CAN-19-1999

    Article  CAS  PubMed  Google Scholar 

  34. Xu, A., Wang, Y., Xu, J. Y., Stejskal, D., Tam, S., Zhang, J., et al. (2006). Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clinical Chemistry, 52(3), 405–413. https://doi.org/10.1373/clinchem.2005.062463

    Article  CAS  PubMed  Google Scholar 

  35. Cao, H., Sekiya, M., Ertunc, M. E., Burak, M. F., Mayers, J. R., White, A., et al. (2013). Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metabolism, 17(5), 768–778. https://doi.org/10.1016/j.cmet.2013.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hao, J., Zhang, Y., Yan, X., Yan, F., Sun, Y., Zeng, J., et al. (2018). Circulating adipose fatty acid binding protein is a new link underlying obesity-associated breast/mammary tumor development. Cell Metabolism, 28(5), 689–705 e685. https://doi.org/10.1016/j.cmet.2018.07.006.

  37. Laurent, V., Guerard, A., Mazerolles, C., Le Gonidec, S., Toulet, A., Nieto, L., et al. (2016). Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nature Communications, 7, 10230. https://doi.org/10.1038/ncomms10230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Louie, S. M., Roberts, L. S., Mulvihill, M. M., Luo, K., & Nomura, D. K. (2013). Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids. Biochimica et Biophysica Acta, 1831(10), 1566–1572. https://doi.org/10.1016/j.bbalip.2013.07.008

    Article  CAS  PubMed  Google Scholar 

  39. Fang, M., Shen, Z., Huang, S., Zhao, L., Chen, S., Mak, T. W., et al. (2010). The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell, 143(5), 711–724. https://doi.org/10.1016/j.cell.2010.10.010

    Article  CAS  PubMed  Google Scholar 

  40. Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., et al. (2012). Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 149(5), 1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kagan, V. E., Mao, G., Qu, F., Angeli, J. P., Doll, S., Croix, C. S., et al. (2017). Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology, 13(1), 81–90. https://doi.org/10.1038/nchembio.2238

    Article  CAS  PubMed  Google Scholar 

  42. Wang, T., Fahrmann, J. F., Lee, H., Li, Y. J., Tripathi, S. C., Yue, C., et al. (2018). JAK/STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metabolism, 27(6), 1357. https://doi.org/10.1016/j.cmet.2018.04.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ye, H., Adane, B., Khan, N., Sullivan, T., Minhajuddin, M., Gasparetto, M., et al. (2016). Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell, 19(1), 23–37. https://doi.org/10.1016/j.stem.2016.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A., & Wu, M. (2011). Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochimica et Biophysica Acta, 1807(6), 726–734. https://doi.org/10.1016/j.bbabio.2010.10.022

    Article  CAS  PubMed  Google Scholar 

  45. Iwamoto, H., Abe, M., Yang, Y., Cui, D., Seki, T., Nakamura, M., et al. (2018). Cancer lipid metabolism confers antiangiogenic drug resistance. Cell Metabolism, 28(1), 104–117 e105. https://doi.org/10.1016/j.cmet.2018.05.005.

  46. Zhang, Y., Daquinag, A., Amaya-Manzanares, F., Sirin, O., Tseng, C., & Kolonin, M. G. (2012). Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Research, 72(20), 5198–5208.

    Article  CAS  Google Scholar 

  47. Ackerman, D., Tumanov, S., Qiu, B., Michalopoulou, E., Spata, M., Azzam, A., et al. (2018). Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation. Cell Rep, 24(10), 2596–2605 e2595. https://doi.org/10.1016/j.celrep.2018.08.015.

  48. Krist, L. F., Eestermans, I. L., Steenbergen, J. J., Hoefsmit, E. C., Cuesta, M. A., Meyer, S., et al. (1995). Cellular composition of milky spots in the human greater omentum: An immunochemical and ultrastructural study. Anatomical Record, 241(2), 163–174. https://doi.org/10.1002/ar.1092410204

    Article  CAS  PubMed  Google Scholar 

  49. Cui, L., Johkura, K., Liang, Y., Teng, R., Ogiwara, N., Okouchi, Y., et al. (2002). Biodefense function of omental milky spots through cell adhesion molecules and leukocyte proliferation. Cell and Tissue Research, 310(3), 321–330. https://doi.org/10.1007/s00441-002-0636-6

    Article  CAS  PubMed  Google Scholar 

  50. Morison, R. (1906). Remarks on some functions of the omentum. British Medical Journal, 1(2350), 76–78. https://doi.org/10.1136/bmj.1.2350.76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Van Vugt, E., Van Rijthoven, E. A., Kamperdijk, E. W., & Beelen, R. H. (1996). Omental milky spots in the local immune response in the peritoneal cavity of rats. Anatomical Record, 244(2), 235–245. https://doi.org/10.1002/(SICI)1097-0185(199602)244:2%3c235::AID-AR11%3e3.0.CO;2-Q

    Article  PubMed  Google Scholar 

  52. Benezech, C., Luu, N. T., Walker, J. A., Kruglov, A. A., Loo, Y., Nakamura, K., et al. (2015). Inflammation-induced formation of fat-associated lymphoid clusters. Nature Immunology, 16(8), 819–828. https://doi.org/10.1038/ni.3215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shimotsuma, M., Simpson-Morgan, M. W., Takahashi, T., & Hagiwara, A. (1992). Activation of omental milky spots and milky spot macrophages by intraperitoneal administration of a streptococcal preparation, OK-432. Cancer Research, 52(19), 5400–5402.

    CAS  PubMed  Google Scholar 

  54. Sorensen, E. W., Gerber, S. A., Sedlacek, A. L., Rybalko, V. Y., Chan, W. M., & Lord, E. M. (2009). Omental immune aggregates and tumor metastasis within the peritoneal cavity. Immunologic Research, 45(2–3), 185–194. https://doi.org/10.1007/s12026-009-8100-2

    Article  CAS  PubMed  Google Scholar 

  55. Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W., Jr. (2003). Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation, 112(12), 1796–1808. https://doi.org/10.1172/JCI19246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., et al. (2003). Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation, 112(12), 1821–1830. https://doi.org/10.1172/JCI19451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Martinez, O., de Victoria, E., Xu, X., Koska, J., Francisco, A. M., Scalise, M., Ferrante, A. W., Jr., et al. (2009). Macrophage content in subcutaneous adipose tissue: Associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians. Diabetes, 58(2), 385–393. https://doi.org/10.2337/db08-0536

    Article  CAS  Google Scholar 

  58. Saberi, M., Woods, N. B., de Luca, C., Schenk, S., Lu, J. C., Bandyopadhyay, G., et al. (2009). Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metabolism, 10(5), 419–429. https://doi.org/10.1016/j.cmet.2009.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z. W., Long, J. M., et al. (2005). IKK-beta links inflammation to obesity-induced insulin resistance. Nature Medicine, 11(2), 191–198. https://doi.org/10.1038/nm1185

    Article  CAS  PubMed  Google Scholar 

  60. Solinas, G., Vilcu, C., Neels, J. G., Bandyopadhyay, G. K., Luo, J. L., Naugler, W., et al. (2007). JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metabolism, 6(5), 386–397. https://doi.org/10.1016/j.cmet.2007.09.011

    Article  CAS  PubMed  Google Scholar 

  61. Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., & Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends in Immunology, 25(12), 677–686. https://doi.org/10.1016/j.it.2004.09.015

    Article  CAS  PubMed  Google Scholar 

  62. Kelly, B., & O’Neill, L. A. (2015). Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Research, 25(7), 771–784. https://doi.org/10.1038/cr.2015.68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Serbulea, V., Upchurch, C. M., Schappe, M. S., Voigt, P., DeWeese, D. E., Desai, B. N., et al. (2018). Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proceedings of the National Academy of Sciences of the United States of America, 115(27), E6254–E6263. https://doi.org/10.1073/pnas.1800544115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xu, X., Grijalva, A., Skowronski, A., van Eijk, M., Serlie, M. J., & Ferrante, A. W., Jr. (2013). Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metabolism, 18(6), 816–830. https://doi.org/10.1016/j.cmet.2013.11.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kratz, M., Coats, B. R., Hisert, K. B., Hagman, D., Mutskov, V., Peris, E., et al. (2014). Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metabolism, 20(4), 614–625. https://doi.org/10.1016/j.cmet.2014.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Krishnan, V., Tallapragada, S., Schaar, B., Kamat, K., Chanana, A. M., Zhang, Y., et al. (2020). Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1. Commun Biol, 3(1), 524. https://doi.org/10.1038/s42003-020-01246-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Etzerodt, A., Moulin, M., Doktor, T. K., Delfini, M., Mossadegh-Keller, N., Bajenoff, M., et al. (2020). Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer. Journal of Experimental Medicine, 217(4). https://doi.org/10.1084/jem.20191869.

  68. Tiwari, P., Blank, A., Cui, C., Schoenfelt, K. Q., Zhou, G., Xu, Y., et al. (2019). Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. Journal of Experimental Medicine, 216(6), 1345–1358. https://doi.org/10.1084/jem.20181616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Linde, N., Casanova-Acebes, M., Sosa, M. S., Mortha, A., Rahman, A., Farias, E., et al. (2018). Macrophages orchestrate breast cancer early dissemination and metastasis. Nature Communications, 9(1), 21. https://doi.org/10.1038/s41467-017-02481-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hao, J., Yan, F., Zhang, Y., Triplett, A., Zhang, Y., Schultz, D. A., et al. (2018). Expression of adipocyte/macrophage fatty acid-binding protein in tumor-associated macrophages promotes breast cancer progression. Cancer Research, 78(9), 2343–2355. https://doi.org/10.1158/0008-5472.CAN-17-2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wensveen, F. M., Jelencic, V., Valentic, S., Sestan, M., Wensveen, T. T., Theurich, S., et al. (2015). NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nature Immunology, 16(4), 376–385. https://doi.org/10.1038/ni.3120

    Article  CAS  PubMed  Google Scholar 

  72. Geller, M. A., Knorr, D. A., Hermanson, D. A., Pribyl, L., Bendzick, L., McCullar, V., et al. (2013). Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Cytotherapy, 15(10), 1297–1306. https://doi.org/10.1016/j.jcyt.2013.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hermanson, D. L., Bendzick, L., Pribyl, L., McCullar, V., Vogel, R. I., Miller, J. S., et al. (2016). Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. Stem Cells, 34(1), 93–101. https://doi.org/10.1002/stem.2230

    Article  CAS  PubMed  Google Scholar 

  74. Nham, T., Poznanski, S. M., Fan, I. Y., Shenouda, M. M., Chew, M. V., Lee, A. J., et al. (2018). Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. Cancer Immunology, Immunotherapy, 67(4), 575–587. https://doi.org/10.1007/s00262-017-2112-x

    Article  CAS  PubMed  Google Scholar 

  75. Sedlacek, A. L., Gerber, S. A., Randall, T. D., van Rooijen, N., Frelinger, J. G., & Lord, E. M. (2013). Generation of a dual-functioning antitumor immune response in the peritoneal cavity. American Journal of Pathology, 183(4), 1318–1328. https://doi.org/10.1016/j.ajpath.2013.06.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Castriconi, R., Cantoni, C., Della Chiesa, M., Vitale, M., Marcenaro, E., Conte, R., et al. (2003). Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 4120–4125. https://doi.org/10.1073/pnas.0730640100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu, J., Wei, M., Becknell, B., Trotta, R., Liu, S., Boyd, Z., et al. (2006). Pro- and antiinflammatory cytokine signaling: Reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity, 24(5), 575–590. https://doi.org/10.1016/j.immuni.2006.03.016

    Article  CAS  PubMed  Google Scholar 

  78. Yaqoob, P., Newsholme, E. A., & Calder, P. C. (1994). Inhibition of natural killer cell activity by dietary lipids. Immunology Letters, 41(2–3), 241–247. https://doi.org/10.1016/0165-2478(94)90140-6

    Article  CAS  PubMed  Google Scholar 

  79. Niavarani, S. R., Lawson, C., Bakos, O., Boudaud, M., Batenchuk, C., Rouleau, S., et al. (2019). Lipid accumulation impairs natural killer cell cytotoxicity and tumor control in the postoperative period. BMC Cancer, 19(1), 823. https://doi.org/10.1186/s12885-019-6045-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Michelet, X., Dyck, L., Hogan, A., Loftus, R. M., Duquette, D., Wei, K., et al. (2018). Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology, 19(12), 1330–1340. https://doi.org/10.1038/s41590-018-0251-7

    Article  CAS  PubMed  Google Scholar 

  81. Talukdar, S., Oh, D. Y., Bandyopadhyay, G., Li, D., Xu, J., McNelis, J., et al. (2012). Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nature Medicine, 18(9), 1407–1412. https://doi.org/10.1038/nm.2885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Elgazar-Carmon, V., Rudich, A., Hadad, N., & Levy, R. (2008). Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. Journal of Lipid Research, 49(9), 1894–1903. https://doi.org/10.1194/jlr.M800132-JLR200

    Article  CAS  PubMed  Google Scholar 

  83. Nijhuis, J., Rensen, S. S., Slaats, Y., van Dielen, F. M., Buurman, W. A., & Greve, J. W. (2009). Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring), 17(11), 2014–2018. https://doi.org/10.1038/oby.2009.113

    Article  CAS  Google Scholar 

  84. Tkalcevic, J., Novelli, M., Phylactides, M., Iredale, J. P., Segal, A. W., & Roes, J. (2000). Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity, 12(2), 201–210. https://doi.org/10.1016/s1074-7613(00)80173-9

    Article  CAS  PubMed  Google Scholar 

  85. Adkison, A. M., Raptis, S. Z., Kelley, D. G., & Pham, C. T. (2002). Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. Journal of Clinical Investigation, 109(3), 363–371. https://doi.org/10.1172/JCI13462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu, Z., Shapiro, S. D., Zhou, X., Twining, S. S., Senior, R. M., Giudice, G. J., et al. (2000). A critical role for neutrophil elastase in experimental bullous pemphigoid. Journal of Clinical Investigation, 105(1), 113–123. https://doi.org/10.1172/JCI3693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jackson-Jones, L. H., Smith, P., Portman, J. R., Magalhaes, M. S., Mylonas, K. J., Vermeren, M. M., et al. (2020). Stromal cells covering omental fat-associated lymphoid clusters trigger formation of neutrophil aggregates to capture peritoneal contaminants. Immunity, 52(4), 700–715 e706. https://doi.org/10.1016/j.immuni.2020.03.011.

  88. Lee, W., Ko, S. Y., Mohamed, M. S., Kenny, H. A., Lengyel, E., & Naora, H. (2019). Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. Journal of Experimental Medicine, 216(1), 176–194. https://doi.org/10.1084/jem.20181170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cui, C., Chakraborty, K., Tang, X. A., Zhou, G., Schoenfelt, K. Q., Becker, K. M., et al. (2021). Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis. Cell, 184(12), 3163–3177 e3121. https://doi.org/10.1016/j.cell.2021.04.016.

  90. Nishimura, S., Manabe, I., Nagasaki, M., Eto, K., Yamashita, H., Ohsugi, M., et al. (2009). CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine, 15(8), 914–920. https://doi.org/10.1038/nm.1964

    Article  CAS  PubMed  Google Scholar 

  91. Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., et al. (2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Medicine, 15(8), 930–939. https://doi.org/10.1038/nm.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., et al. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature Medicine, 15(8), 921–929. https://doi.org/10.1038/nm.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang, Z., Aguilar, E. G., Luna, J. I., Dunai, C., Khuat, L. T., Le, C. T., et al. (2019). Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine, 25(1), 141–151. https://doi.org/10.1038/s41591-018-0221-5

    Article  CAS  PubMed  Google Scholar 

  94. Liu, Y., Metzinger, M. N., Lewellen, K. A., Cripps, S. N., Carey, K. D., Harper, E. I., et al. (2015). Obesity contributes to ovarian cancer metastatic success through increased lipogenesis, enhanced vascularity, and decreased infiltration of M1 macrophages. Cancer Research, 75(23), 5046–5057. https://doi.org/10.1158/0008-5472.CAN-15-0706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang, C., Yue, C., Herrmann, A., Song, J., Egelston, C., Wang, T., et al. (2020). STAT3 activation-induced fatty acid oxidation in CD8(+) T effector cells is critical for obesity-promoted breast tumor growth. Cell Metabolism, 31(1), 148–161 e145. https://doi.org/10.1016/j.cmet.2019.10.013.

  96. Ma, X., Xiao, L., Liu, L., Ye, L., Su, P., Bi, E., et al. (2021). CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metabolism, 33(5), 1001–1012 e1005. https://doi.org/10.1016/j.cmet.2021.02.015.

Download references

Funding

This study is funded by DOD pilot award (W81XWH2110376) to Abir Mukherjee (A.M) and NIH grant (R01CA169604, R35CA264619) awarded to Ernst Lengyel (E.L). We thank Gail Isenberg for editing the manuscript. Illustrations were generated using biorender.com.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA

    Abir Mukherjee, Agnes J. Bilecz & Ernst Lengyel

Authors
  1. Abir Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Agnes J. Bilecz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ernst Lengyel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ernst Lengyel.

Ethics declarations

Conflict of interest

E. L. receives research funding for preclinical ovarian cancer studies from Abbvie and Arsenal Bioscience outside of the scope of this work and is co-inventor on a patent proposing to use FABP inhibitors for ovarian cancer treatment. A. M. and A. J. B. have no conflicts to report.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mukherjee, A., Bilecz, A.J. & Lengyel, E. The adipocyte microenvironment and cancer. Cancer Metastasis Rev 41, 575–587 (2022). https://doi.org/10.1007/s10555-022-10059-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-022-10059-x

Keywords

Search

Navigation