Abstract
Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical observations, including effects of diet and lifestyle, systemic changes in energy balance and hormonal regulation and activation of signalling by growth factors and cytokines and other components of the immune system. Over the past decade, research on obesity has shifted towards investigating the role of peri-prostatic white adipose tissue as an important source of locally produced factors that stimulate prostate cancer progression. Cells that comprise white adipose tissue, the adipocytes and their progenitor adipose stromal cells (ASCs), which proliferate to accommodate white adipose tissue expansion in obesity, have been identified as important drivers of obesity-associated cancer progression. Accumulating evidence suggests that adipocytes are a source of lipids that are used by adjacent prostate cancer cells. However, results of preclinical studies indicate that ASCs promote tumour growth by remodelling extracellular matrix and supporting neovascularization, contributing to the recruitment of immunosuppressive cells, and inducing epithelial–mesenchymal transition through paracrine signalling. Because epithelial–mesenchymal transition is associated with cancer chemotherapy resistance and metastasis, ASCs are considered to be potential targets of therapies that could be developed to suppress cancer aggressiveness in patients with obesity.
Key points
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Obesity is associated with aggressive and high-grade prostate cancer, as well as increased mortality.
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Peri-prostatic white adipose tissue expansion in obesity leads to induced secretion of adipokines, cytokines and chemokines from adipocytes, adipose stromal cells (ASCs) and other cells in the tumour stroma.
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ASCs recruited to tumours act as cancer-associated fibroblasts in the tumour microenvironment to promote vascularization, recruit immunosuppressive leukocytes, remodel extracellular matrix and induce epithelial–mesenchymal transition, which promotes cancer aggressiveness and therapy resistance.
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The prevalence of obesity continues to increase; thus, manipulating events associated with white adipose tissue overgrowth that promote cancer progression could mitigate the increased risk of prostate cancer aggressiveness associated with obesity. However, the potentially negative consequences of therapies aimed at white adipose tissue need to be carefully considered.
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References
Panuganti, K. K., Nguyen, M. & Kshirsagar, R. K. Obesity. StatPearls https://www.ncbi.nlm.nih.gov/books/NBK459357/ (2022).
Stierman B, et al. National Health and Nutrition Examination Survey 2017–March 2020 prepandemic data files — development of files and prevalence estimates for selected health outcomes (National Center for Health Statistics, 2021).
World Health Organization. Obesity and overweight. WHO https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (2021).
Kelly, T., Yang, W., Chen, C. S., Reynolds, K. & He, J. Global burden of obesity in 2005 and projections to 2030. Int. J. Obes. 32, 1431–1437 (2008).
Jo, J. et al. Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput. Biol. 5, e1000324 (2009).
Longo, M. et al. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int. J. Mol. Sci. 20, 2358 (2019).
Lionetti, L. et al. From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr. Metab. Cardiovasc. Dis. 19, 146–152 (2009).
Jo, J. et al. Hypertrophy-driven adipocyte death overwhelms recruitment under prolonged weight gain. Biophys. J. 99, 3535–3544 (2010).
Park, Y. W. et al. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch. Intern. Med. 163, 427–436 (2003).
Gariballa, S., Alkaabi, J., Yasin, J. & Al Essa, A. Total adiponectin in overweight and obese subjects and its response to visceral fat loss. BMC Endocr. Disord. 19, 55 (2019).
Hursting, S. D. et al. Obesity, energy balance, and cancer: new opportunities for prevention. Cancer Prev. Res. 5, 1260–1272 (2012).
Nijhawans, P., Behl, T. & Bhardwaj, S. Angiogenesis in obesity. Biomed. Pharmacother. 126, 110103 (2020).
Saha, A. et al. Proinflammatory CXCL12-CXCR4/CXCR7 signaling axis drives Myc-induced prostate cancer in obese mice. Cancer Res. 77, 5158–5168 (2017).
Blando, J., Saha, A., Kiguchi, K. & DiGiovanni, J. in Obesity, Inflammation and Cancer Vol. 7 (eds Dannenberg, A. J. & Berger, N. A.) 235–256 (Springer, 2013).
Hursting, S. D. & Berger, N. A. Energy balance, host-related factors, and cancer progression. J. Clin. Oncol. 28, 4058–4065 (2010).
Poirier, P. et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Arterioscler. Thromb. Vasc. Biol. 26, 968–976 (2006).
American Cancer Society. Global Cancer Facts & Figures 4th edn (American Cancer Society, 2018).
Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 72, 7–33 (2022).
American Cancer Society. Key statistics for prostate cancer. American Cancer Society https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html (2023).
Roberts, D. L., Dive, C. & Renehan, A. G. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301–316 (2010).
Renehan, A. G., Roberts, D. L. & Dive, C. Obesity and cancer: pathophysiological and biological mechanisms. Arch. Physiol. Biochem. 114, 71–83 (2008).
Pischon, T., Nothlings, U. & Boeing, H. Obesity and cancer. Proc. Nutr. Soc. 67, 128–145 (2008).
Strom, S. S. et al. Influence of obesity on biochemical and clinical failure after external-beam radiotherapy for localized prostate cancer. Cancer 107, 631–639 (2006).
Strom, S. S. et al. Obesity, weight gain, and risk of biochemical failure among prostate cancer patients following prostatectomy. Clin. Cancer Res. 11, 6889–6894 (2005).
Nomura, A. M. Body size and prostate cancer. Epidemiol. Rev. 23, 126–131 (2001).
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Park, J., Euhus, D. M. & Scherer, P. E. Paracrine and endocrine effects of adipose tissue on cancer development and progression. Endocr. Rev. 32, 550–570 (2011).
Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer–mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
Fujita, K., Hayashi, T., Matsushita, M., Uemura, M. & Nonomura, N. Obesity, inflammation, and prostate cancer. J. Clin. Med. 8, 201 (2019).
Hsing, A. W., Sakoda, L. C. & Chua, S. Jr Obesity, metabolic syndrome, and prostate cancer. Am. J. Clin. Nutr. 86, s843–s857 (2007).
Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).
Toren, P. & Venkateswaran, V. Periprostatic adipose tissue and prostate cancer progression: new insights into the tumor microenvironment. Clin. Genitourin. Cancer 12, 21–26 (2014).
Zhang, T. et al. CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat. Commun. 7, 11674 (2016).
Laurent, V. et al. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nat. Commun. 7, 10230 (2016).
Ramos-Nino, M. E. The role of chronic inflammation in obesity-associated cancers. ISRN Oncol. 2013, 697521 (2013).
Lauby-Secretan, B. et al. Body fatness and cancer — viewpoint of the IARC Working Group. N. Engl. J. Med. 375, 794–798 (2016).
Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
Stocks, T. et al. Cohort profile: the metabolic syndrome and cancer project (Me-Can). Int. J. Epidemiol. 39, 660–667 (2010).
Eheman, C. et al. Annual Report to the Nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer 118, 2338–2366 (2012).
Flegal, K. M., Carroll, M. D., Kit, B. K. & Ogden, C. L. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307, 491–497 (2012).
Finucane, M. M. et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377, 557–567 (2011).
Fryar, C. D., Carroll, M. D. & Afful J. Prevalence of overweight, obesity, and severe obesity among adults aged 20 and over: United States, 1960–1962 through 2017–2018 (National Center for Health Statistics, 2021).
Ogden, C.L. & Carroll, M. D. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960–1962 through 2007–2008 (CDC, 2010).
Porter, M. P. & Stanford, J. L. Obesity and the risk of prostate cancer. Prostate 62, 316–321 (2005).
Flavin, R., Zadra, G. & Loda, M. Metabolic alterations and targeted therapies in prostate cancer. J. Pathol. 223, 283–294 (2011).
Wright, M. E. et al. Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality. Cancer 109, 675–684 (2007).
Bassett, J. K. et al. Weight change and prostate cancer incidence and mortality. Int. J. Cancer 131, 1711–1719 (2012).
Rodriguez, C. et al. Body mass index, weight change, and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol. Biomark. Prev. 16, 63–69 (2007).
Rodriguez, C. et al. Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States. Cancer Epidemiol. Biomark. Prev. 10, 345–353 (2001).
Perez-Cornago, A., Dunneram, Y., Watts, E. L., Key, T. J. & Travis, R. C. Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies. BMC Med. 20, 143 (2022).
Dickerman, B. A. et al. Weight change, obesity and risk of prostate cancer progression among men with clinically localized prostate cancer. Int. J. Cancer 141, 933–944 (2017).
Hsing, A. W. et al. Body size and prostate cancer: a population-based case-control study in China. Cancer Epidemiol. Biomark. Prev. 9, 1335–1341 (2000).
Guerrios-Rivera, L. et al. Is Body Mass Index the best adiposity measure for prostate cancer risk? Results from a veterans affairs biopsy cohort. Urology 105, 129–135 (2017).
Spitz, M. R. et al. Epidemiologic determinants of clinically relevant prostate cancer. Int. J. Cancer 89, 259–264 (2000).
Mandair, D., Rossi, R. E., Pericleous, M., Whyand, T. & Caplin, M. E. Prostate cancer and the influence of dietary factors and supplements: a systematic review. Nutr. Metab. 11, 30 (2014).
Yang, M. et al. Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality. Cancer Prev. Res. 8, 545–551 (2015).
Aronson, W. J. et al. Growth inhibitory effect of low fat diet on prostate cancer cells: results of a prospective, randomized dietary intervention trial in men with prostate cancer. J. Urol. 183, 345–350 (2010).
Venkateswaran, V. & Klotz, L. H. Diet and prostate cancer: mechanisms of action and implications for chemoprevention. Nat. Rev. Urol. 7, 442–453 (2010).
Michaud, D. S. et al. A prospective study on intake of animal products and risk of prostate cancer. Cancer Causes Control 12, 557–567 (2001).
Richman, E. L. et al. Fat intake after diagnosis and risk of lethal prostate cancer and all-cause mortality. JAMA Intern. Med. 173, 1318–1326 (2013).
Pelser, C., Mondul, A. M., Hollenbeck, A. R. & Park, Y. Dietary fat, fatty acids, and risk of prostate cancer in the NIH-AARP diet and health study. Cancer Epidemiol. Biomark. Prev. 22, 697–707 (2013).
Strom, S. S. et al. Saturated fat intake predicts biochemical failure after prostatectomy. Int. J. Cancer 122, 2581–2585 (2008).
Allott, E. H. et al. Saturated fat intake and prostate cancer aggressiveness: results from the population-based North Carolina-Louisiana prostate cancer project. Prostate Cancer Prostatic Dis. 20, 48–54 (2017).
Freedland, S. J. & Aronson, W. J. Examining the relationship between obesity and prostate cancer. Rev. Urol. 6, 73–81 (2004).
Giovannucci, E. & Michaud, D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132, 2208–2225 (2007).
Gong, Z. et al. Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial. Cancer Epidemiol. Biomark. Prev. 15, 1977–1983 (2006).
Giovannucci, E., Rimm, E. B., Stampfer, M. J., Colditz, G. A. & Willett, W. C. Height, body weight, and risk of prostate cancer. Cancer Epidemiol. Biomark. Prev. 6, 557–563 (1997).
Engeland, A., Tretli, S. & Bjorge, T. Height, body mass index, and prostate cancer: a follow-up of 950000 Norwegian men. Br. J. Cancer 89, 1237–1242 (2003).
Giovannucci, E. et al. Body mass index and risk of prostate cancer in U.S. health professionals. J. Natl Cancer Inst. 95, 1240–1244 (2003).
Pasquali, R. et al. Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism 40, 101–104 (1991).
Banez, L. L. et al. Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer. JAMA 298, 2275–2280 (2007).
Freedland, S. J. Obesity and prostate cancer: a growing problem. Clin. Cancer Res. 11, 6763–6766 (2005).
Baillargeon, J. et al. The association of body mass index and prostate-specific antigen in a population-based study. Cancer 103, 1092–1095 (2005).
Walsh, P. C. Observed effect of age and body mass index on total and complexed PSA: analysis from a National Screening Program. J. Urol. 174, 1825–1826 (2005).
Barrington, W. E. et al. 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).
Chornokur, G. et al. Variation in HNF1B and obesity may influence prostate cancer risk in African American men: a pilot study. Prostate Cancer 2013, 384594 (2013).
Dasari, S. S. et al. Circadian rhythm disruption as a contributor to racial disparities in prostate cancer. Cancers 14, 5116 (2022).
Farrell, J., Petrovics, G., McLeod, D. G. & Srivastava, S. Genetic and molecular differences in prostate carcinogenesis between African American and Caucasian American men. Int. J. Mol. Sci. 14, 15510–15531 (2013).
Powell, I. J. & Bollig-Fischer, A. Minireview: the molecular and genomic basis for prostate cancer health disparities. Mol. Endocrinol. 27, 879–891 (2013).
Bradbury, B. D., Wilk, J. B. & Kaye, J. A. Obesity and the risk of prostate cancer (United States). Cancer Causes Control 16, 637–641 (2005).
Golabek, T. et al. Obesity and prostate cancer incidence and mortality: a systematic review of prospective cohort studies. Urol. Int. 92, 7–14 (2014).
Moller, H. et al. Prostate cancer incidence, clinical stage and survival in relation to obesity: a prospective cohort study in Denmark. Int. J. Cancer 136, 1940–1947 (2015).
Tzenios, N., Tazanios, M. E. & Chahine, M. The impact of body mass index on prostate cancer: an updated systematic review and meta-analysis. Medicine 101, e30191 (2022).
Vidal, A. C. et al. Obesity and prostate cancer-specific mortality after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Prostate Cancer Prostatic Dis. 20, 72–78 (2017).
Keto, C. J. et al. 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).
Cao, Y. & Ma, J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev. Res. 4, 486–501 (2011).
Efstathiou, J. A., Chen, M. H., Renshaw, A. A., Loffredo, M. J. & D’Amico, A. V. Influence of body mass index on prostate-specific antigen failure after androgen suppression and radiation therapy for localized prostate cancer. Cancer 109, 1493–1498 (2007).
Jayachandran, J. et al. Obesity as a predictor of adverse outcome across black and white race: results from the shared equal access regional cancer hospital (SEARCH) database. Cancer 115, 5263–5271 (2009).
Hisasue, S. et al. Influence of body mass index and total testosterone level on biochemical recurrence following radical prostatectomy. Jpn. J. Clin. Oncol. 38, 129–133 (2008).
Spangler, E. et al. Association of obesity with tumor characteristics and treatment failure of prostate cancer in African-American and European American men. J. Urol. 178, 1939–1944 (2007).
Tourinho-Barbosa, R. et al. Biochemical recurrence after radical prostatectomy: what does it mean. Int. Braz. J. Urol. 44, 14–21 (2018).
Taplin, M. E. Biochemical (prostate-specific antigen) relapse: an oncologist’s perspective. Rev. Urol. 5, S3–S13 (2003).
Pound, C. R. et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281, 1591–1597 (1999).
Manna, F. et al. Metastases in prostate cancer. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a033688 (2019).
Nuhn, P. et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. Eur. Urol. 75, 88–99 (2019).
Damodaran, S., Lang, J. M. & Jarrard, D. F. Targeting metastatic hormone sensitive prostate cancer: chemohormonal therapy and new combinatorial approaches. J. Urol. 201, 876–885 (2019).
Wang, L. S. et al. Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer. Cancer 121, 3010–3017 (2015).
Hanley, M. J., Abernethy, D. R. & Greenblatt, D. J. Effect of obesity on the pharmacokinetics of drugs in humans. Clin. Pharmacokinet. 49, 71–87 (2010).
Sheng, X. et al. Adipocytes sequester and metabolize the chemotherapeutic daunorubicin. Mol. Cancer Res. 15, 1704–1713 (2017).
Lavalette, C. et al. Abdominal obesity and prostate cancer risk: epidemiological evidence from the EPICAP study. Oncotarget 9, 34485–34494 (2018).
De Nunzio, C. et al. Abdominal obesity as risk factor for prostate cancer diagnosis and high grade disease: a prospective multicenter Italian cohort study. Urol. Oncol. 31, 997–1002 (2013).
Giovannucci, E. et al. A prospective study of dietary fat and risk of prostate cancer. J. Natl Cancer Inst. 85, 1571–1579 (1993).
Trayhurn, P. & Wood, I. S. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br. J. Nutr. 92, 347–355 (2004).
Corvera, S. Cellular heterogeneity in adipose tissues. Annu. Rev. Physiol. 83, 257–278 (2021).
Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).
Ribeiro, R. et al. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro. J. Exp. Clin. Cancer Res. 31, 32 (2012).
van Roermund, J. G. et al. Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients. BJU Int. 107, 1775–1779 (2011).
Bi, S. & Li, L. Browning of white adipose tissue: role of hypothalamic signaling. Ann. NY Acad. Sci. 1302, 30–34 (2013).
Tilg, H. & Moschen, A. R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat. Rev. Immunol. 6, 772–783 (2006).
Friedman, J. M. Obesity: causes and control of excess body fat. Nature 459, 340–342 (2009).
Nagle, C. M. et al. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium. Br. J. Cancer 113, 817–826 (2015).
Sun, K., Kusminski, C. M. & Scherer, P. E. Adipose tissue remodeling and obesity. J. Clin. Invest. 121, 2094–2101 (2011).
Zhang, Y. et al. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res. 72, 5198–5208 (2012).
Ribeiro, R. et al. Human periprostatic white adipose tissue is rich in stromal progenitor cells and a potential source of prostate tumor stroma. Exp. Biol. Med. 237, 1155–1162 (2012).
Ribeiro, R. J. et al. Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile. Cell Physiol. Biochem. 29, 233–240 (2012).
Finley, D. S. et al. Periprostatic adipose tissue as a modulator of prostate cancer aggressiveness. J. Urol. 182, 1621–1627 (2009).
Nassar, Z. D. et al. Peri-prostatic adipose tissue: the metabolic microenvironment of prostate cancer. BJU Int. 121, 9–21 (2018).
Cozzo, A. J., Fuller, A. M. & Makowski, L. Contribution of adipose tissue to development of cancer. Compr. Physiol. 8, 237–282 (2017).
Uehara, H. et al. Adipose tissue: critical contributor to the development of prostate cancer. J. Med. Invest. 65, 9–17 (2018).
Bissell, M. J. & Radisky, D. Putting tumours in context. Nat. Rev. Cancer 1, 46–54 (2001).
Walz, J. et al. 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).
Sung, M. T., Eble, J. N. & Cheng, L. Invasion of fat justifies assignment of stage pT3a in prostatic adenocarcinoma. Pathology 38, 309–311 (2006).
Strong, A. L., Burow, M. E., Gimble, J. M. & Bunnell, B. A. Concise review: the obesity cancer paradigm: exploration of the interactions and crosstalk with adipose stem cells. Stem Cell 33, 318–326 (2015).
Sun, K., Tordjman, J., Clement, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).
Trayhurn, P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 93, 1–21 (2013).
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A. & Smith, U. Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Physiol. Rev. 98, 1911–1941 (2018).
Nishimura, S. et al. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J. Clin. Invest. 118, 710–721 (2008).
Murano, I. et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J. Lipid Res. 49, 1562–1568 (2008).
Carroll, V. A. & Ashcroft, M. Targeting the molecular basis for tumour hypoxia. Expert Rev. Mol. Med. 7, 1–16 (2005).
Cao, Y. Angiogenesis modulates adipogenesis and obesity. J. Clin. Invest. 117, 2362–2368 (2007).
Lijnen, H. R. Angiogenesis and obesity. Cardiovasc. Res. 78, 286–293 (2008).
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).
Himbert, C. et al. Signals from the adipose microenvironment and the obesity-cancer link — a systematic review. Cancer Prev. Res. 10, 494–506 (2017).
Ribeiro, R. et al. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue. BMC Med. 10, 108 (2012).
Bourin, P. et al. 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 and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15, 641–648 (2013).
Catalan, V., Gomez-Ambrosi, J., Rodriguez, A. & Fruhbeck, G. Adipose tissue immunity and cancer. Front. Physiol. 4, 275 (2013).
Gomez-Ambrosi, J. et al. Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity. Int. J. Obes. 36, 286–294 (2012).
Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
McLaughlin, T., Ackerman, S. E., Shen, L. & Engleman, E. Role of innate and adaptive immunity in obesity-associated metabolic disease. J. Clin. Invest. 127, 5–13 (2017).
Cancello, R. et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54, 2277–2286 (2005).
Bruun, J. M., Lihn, A. S., Pedersen, S. B. & Richelsen, B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J. Clin. Endocrinol. Metab. 90, 2282–2289 (2005).
Khodabandehloo, H., Gorgani-Firuzjaee, S., Panahi, G. & Meshkani, R. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl. Res. 167, 228–256 (2016).
Ramkhelawon, B. et al. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat. Med. 20, 377–384 (2014).
Parisi, L. et al. Macrophage polarization in chronic inflammatory diseases: killers or builders? J. Immunol. Res. 2018, 8917804 (2018).
Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).
Seijkens, T., Kusters, P., Chatzigeorgiou, A., Chavakis, T. & Lutgens, E. Immune cell crosstalk in obesity: a key role for costimulation? Diabetes 63, 3982–3991 (2014).
Gordon, S. & Taylor, P. R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).
Castoldi, A., Naffah de Souza, C., Camara, N. O. & Moraes-Vieira, P. M. The macrophage switch in obesity development. Front. Immunol. 6, 637 (2015).
Phieler, J. et al. The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance. J. Immunol. 191, 4367–4374 (2013).
Choe, S. S., Huh, J. Y., Hwang, I. J., Kim, J. I. & Kim, J. B. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front. Endocrinol. 7, 30 (2016).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Conde, J. et al. Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Biofactors 37, 413–420 (2011).
Lehr, S., Hartwig, S. & Sell, H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin. Appl. 6, 91–101 (2012).
Deng, Y. & Scherer, P. E. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann. NY Acad. Sci. 1212, E1–E19 (2010).
Mistry, T., Digby, J. E., Desai, K. M. & Randeva, H. S. Obesity and prostate cancer: a role for adipokines. Eur. Urol. 52, 46–53 (2007).
Nunemaker, C. S. et al. Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function. J. Endocrinol. 222, 267–276 (2014).
Miyake, M., Lawton, A., Goodison, S., Urquidi, V. & Rosser, C. J. Chemokine (C-X-C motif) ligand 1 (CXCL1) protein expression is increased in high-grade prostate cancer. Pathol. Res. Pract. 210, 74–78 (2014).
Straczkowski, M. et al. Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-α system. J. Clin. Endocrinol. Metab. 87, 4602–4606 (2002).
Araki, S. et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res. 67, 6854–6862 (2007).
Polimera, H. V. et al. Plasma IL-8 and PD-L1 and overall survival in metastatic castration-resistant prostate cancer patients (mCRPC). J. Clin. Oncol. 38, e1755 (2020).
Maynard, J. P. et al. IL8 expression is associated with prostate cancer aggressiveness and androgen receptor loss in primary and metastatic prostate cancer. Mol. Cancer Res. 18, 153–165 (2020).
Walz, A., Peveri, P., Aschauer, H. & Baggiolini, M. Purification and amino acid sequencing of NAF, a novel neutrophil-activating factor produced by monocytes. Biochem. Biophys. Res. Commun. 149, 755–761 (1987).
Hebert, C. A. & Baker, J. B. Interleukin-8: a review. Cancer Invest. 11, 743–750 (1993).
Holmes, W. E., Lee, J., Kuang, W. J., Rice, G. C. & Wood, W. I. Structure and functional expression of a human interleukin-8 receptor. Science. 1991. 253: 1278–1280. J. Immunol. 183, 2895–2897 (2009).
Morohashi, H. et al. Expression of both types of human interleukin-8 receptors on mature neutrophils, monocytes, and natural killer cells. J. Leukoc. Biol. 57, 180–187 (1995).
Kim, S. J. et al. Expression of interleukin-8 correlates with angiogenesis, tumorigenicity, and metastasis of human prostate cancer cells implanted orthotopically in nude mice. Neoplasia 3, 33–42 (2001).
Domanska, U. M. et al. A review on CXCR4/CXCL12 axis in oncology: no place to hide. Eur. J. Cancer 49, 219–230 (2013).
Sun, X. et al. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 29, 709–722 (2010).
Su, F., Ahn, S., Saha, A., DiGiovanni, J. & Kolonin, M. G. Adipose stromal cell targeting suppresses prostate cancer epithelial-mesenchymal transition and chemoresistance. Oncogene 38, 1979–1988 (2019).
Ahn, S., Saha, A., Kolonin, M. G., DiGiovanni, J. Signaling via both CXCR4 and CXCR7 in prostate cancer cells promotes tumor progression and underlies obesity-associated epithelial-mesenchymal transition. Oncogene 41, 4633-4644 (2022).
Wang, J. et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J. Biol. Chem. 283, 4283–4294 (2008).
Santos-Alvarez, J., Goberna, R. & Sanchez-Margalet, V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell. Immunol. 194, 6–11 (1999).
Fruhbeck, G. Intracellular signalling pathways activated by leptin. Biochem. J. 393, 7–20 (2006).
Kiguchi, N., Maeda, T., Kobayashi, Y., Fukazawa, Y. & Kishioka, S. Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem. Biophys. Res. Commun. 384, 311–315 (2009).
Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).
Weidner, N., Carroll, P. R., Flax, J., Blumenfeld, W. & Folkman, J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am. J. Pathol. 143, 401–409 (1993).
Duque, J. L. et al. Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. Urology 54, 523–527 (1999).
Woollard, D. J. et al. Differential expression of VEGF ligands and receptors in prostate cancer. Prostate 73, 563–572 (2013).
Simpson, A. J., Booth, N. A., Moore, N. R. & Bennett, B. Distribution of plasminogen activator inhibitor (PAI-1) in tissues. J. Clin. Pathol. 44, 139–143 (1991).
Wang, W. & Seale, P. Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17, 691–702 (2016).
Gao, Z., Daquinag, A. C., Su, F., Snyder, B. & Kolonin, M. G. PDGFR/PDGFRβ signaling balance modulates progenitor cell differentiation into white and beige adipocytes. Development 145, dev155861 (2018).
Eckel-Mahan, K., Ribas Latre, A. & Kolonin, M. G. Adipose stromal cell expansion and exhaustion: mechanisms and consequences. Cells 9, 863 (2020).
Magi-Galluzzi, C. et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic extension, lymphovascular invasion and locally advanced disease. Mod. Pathol. 24, 26–38 (2011).
Kapoor, J. et al. Extraprostatic extension into periprostatic fat is a more important determinant of prostate cancer recurrence than an invasive phenotype. J. Urol. 190, 2061–2066 (2013).
Wan, X. et al. Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci. Transl Med. 6, 122–125 (2014).
Hagglof, C. & Bergh, A. The stroma — a key regulator in prostate function and malignancy. Cancers 4, 531–548 (2012).
Dawson, M. R., Chae, S. S., Jain, R. K. & Duda, D. G. Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression. Am. J. Cancer Res. 1, 144–154 (2011).
Du, R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).
Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Galie, M. et al. Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice. Oncogene 27, 2542–2545 (2007).
Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).
Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).
Peng, Y. C., Levine, C. M., Zahid, S., Wilson, E. L. & Joyner, A. L. Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration. Proc. Natl Acad. Sci. USA 110, 20611–20616 (2013).
Kolonin, M. G. Progenitor cell mobilization from extramedullary organs. Methods Mol. Biol. 904, 243–252 (2012).
Kidd, S. et al. Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS ONE 7, e30563 (2012).
Placencio, V. R., Li, X., Sherrill, T. P., Fritz, G. & Bhowmick, N. A. Bone marrow derived mesenchymal stem cells incorporate into the prostate during regrowth. PLoS ONE 5, e12920 (2010).
Jung, Y. et al. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat. Commun. 4, 1795 (2013).
Fukumura, D. & Jain, R. K. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc. Res. 74, 72–84 (2007).
Borriello, L. & DeClerck, Y. A. Tumor microenvironment and therapeutic resistance process. Med. Sci. 30, 445–451 (2014).
Wels, J., Kaplan, R. N., Rafii, S. & Lyden, D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 22, 559–574 (2008).
San Martin, R. et al. Recruitment of CD34+ fibroblasts in tumor-associated reactive stroma: the reactive microvasculature hypothesis. Am. J. Pathol. 184, 1860–1870 (2014).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Kiskowski, M. A. et al. Role for stromal heterogeneity in prostate tumorigenesis. Cancer Res. 71, 3459–3470 (2011).
Lu, P., Weaver, V. M. & Werb, Z. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406 (2012).
Kolonin, M. G., Evans, K. W., Mani, S. A. & Gomer, R. H. Alternative origins of stroma in normal organs and disease. Stem Cell Res. 8, 312–323 (2012).
Nieman, K. M., Romero, I. L., Van Houten, B. & Lengyel, E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta 1831, 1533–15341 (2013).
Zhu, K., Cai, L., Cui, C., de Los Toyos, J. R. & Anastassiou, D. Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts. PLoS Comput. Biol. 17, e1009228 (2021).
Zhu, Q. et al. Adipocyte mesenchymal transition contributes to mammary tumor progression. Cell Rep. 40, 111362 (2022).
Bellows, C. F., Zhang, Y., Chen, J., Frazier, M. L. & Kolonin, M. G. Circulation of progenitor cells in obese and lean colorectal cancer patients. Cancer Epidemiol. Biomark. Prev. 20, 2461–2468 (2011).
Bellows, C. F., Zhang, Y., Simmons, P. J., Khalsa, A. S. & Kolonin, M. G. Influence of BMI on level of circulating progenitor cells. Obesity 19, 1722–1726 (2011).
Zhang, Y. et al. White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Res. 69, 5259–5266 (2009).
Klopp, A. H. et al. Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors. Clin. Cancer Res. 18, 771–782 (2012).
Sirin, O. & Kolonin, M. G. Treatment of obesity as a potential complementary approach to cancer therapy. Drug Discov. Today 18, 567–573 (2013).
Bertolini, F., Lohsiriwat, V., Petit, J. Y. & Kolonin, M. G. Adipose tissue cells, lipotransfer and cancer: a challenge for scientists, oncologists and surgeons. Biochim. Biophys. Acta 1826, 209–214 (2012).
Bertolini, F., Petit, J. Y. & Kolonin, M. G. Stem cells from adipose tissue and breast cancer: hype, risks and hope. Br. J. Cancer 112, 419–423 (2015).
Nie, J. et al. Combinatorial peptides identify α5β1 integrin as a receptor for the matricellular protein SPARC on adipose stromal cells. Stem Cell 26, 2735–2745 (2008).
Tseng, C. & Kolonin, M. G. Proteolytic isoforms of SPARC induce adipose stromal cell mobilization in obesity. Stem Cell 34, 174–190 (2015).
Rossi, D. & Zlotnik, A. The biology of chemokines and their receptors. Annu. Rev. Immunol. 18, 217–242 (2000).
Laird, D. J., von Andrian, U. H. & Wagers, A. J. Stem cell trafficking in tissue development, growth, and disease. Cell 132, 612–630 (2008).
Kolonin, M. G. & DiGiovanni, J. The role of adipose stroma in prostate cancer aggressiveness. Transl. Androl. Urol. 8, S348–S350 (2019).
Ahn, S., Saha, A., Clark, R., Kolonin, M. G. & DiGiovanni, J. CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells. Oncogene 41, 4633–4644 (2022).
Zhang, Y. & Kolonin, M. G. Cytokine signaling regulating adipose stromal cell trafficking. Adipocyte 5, 369–374 (2016).
Kaplan, J. L. et al. Adipocyte progenitor cells initiate monocyte chemoattractant protein-1-mediated macrophage accumulation in visceral adipose tissue. Mol. Metab. 4, 779–794 (2015).
Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008).
Iyengar, N. M. et al. Metabolic obesity, adipose inflammation and elevated breast aromatase in women with normal body mass index. Cancer Prev. Res. 10, 235–243 (2017).
Lengyel, E., Makowski, L., DiGiovanni, J. & Kolonin, M. G. Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4, 374–384 (2018).
Ling, L. et al. Obesity-associated adipose stromal cells promote breast cancer invasion through direct cell contact and ECM remodeling. Adv. Funct. Mater. 30, 1910650 (2020).
Zyromski, N. J. et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery 146, 258–263 (2009).
Orecchioni, S. et al. Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer. Cancer Res. 73, 5880–5891 (2013).
Rowan, B. G. et al. Human adipose tissue-derived stromal/stem cells promote migration and early metastasis of triple negative breast cancer xenografts. PLoS ONE 9, e89595 (2014).
Martin-Padura, I. et al. The white adipose tissue used in lipotransfer procedures is a rich reservoir of CD34+ progenitors able to promote cancer progression. Cancer Res. 72, 325–334 (2012).
Zhao, M., Dumur, C. I., Holt, S. E., Beckman, M. J. & Elmore, L. W. Multipotent adipose stromal cells and breast cancer development: think globally, act locally. Mol. Carcinog. 49, 923–927 (2010).
Picon-Ruiz, M. et al. 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).
Nowicka, A. et al. Human omental-derived adipose stem cells increase ovarian cancer proliferation, migration, and chemoresistance. PLoS ONE 8, e81859 (2013).
Salimian Rizi, B. et al. Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells. Cancer Res. 75, 456–4571 (2015).
Duong, M. N. et al. Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity. Breast Cancer Res. 17, 57–63 (2015).
Houthuijzen, J. M., Daenen, L. G., Roodhart, J. M. & Voest, E. E. The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br. J. Cancer 106, 1901–1906 (2012).
Chen, D. et al. Paracrine factors from adipose-mesenchymal stem cells enhance metastatic capacity through Wnt signaling pathway in a colon cancer cell co-culture model. Cancer Cell Int. 15, 42–47 (2015).
Meurette, O. & Mehlen, P. Notch signaling in the tumor microenvironment. Cancer Cell 34, 536–548 (2018).
Danza, G. et al. Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer. Int. J. Cancer 133, 2577–2586 (2013).
Kwon, O. J. et al. Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nat. Commun. 5, 4416–4422 (2014).
Capaccione, K. M. & Pine, S. R. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis 34, 1420–1430 (2013).
Santagata, S. et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 64, 6854–6857 (2004).
Carvalho, F. L., Simons, B. W., Eberhart, C. G. & Berman, D. M. Notch signaling in prostate cancer: a moving target. Prostate 74, 933–945 (2014).
Zhu, H., Zhou, X., Redfield, S., Lewin, J. & Miele, L. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. Am. J. Transl. Res. 5, 368–378 (2013).
Bin Hafeez, B. et al. Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin. Cancer Res. 15, 452–459 (2009).
Xishan, Z. et al. Jagged-2 enhances immunomodulatory activity in adipose derived mesenchymal stem cells. Sci. Rep. 5, 14284 (2015).
Shi, D. et al. Human adipose tissue-derived mesenchymal stem cells facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-κB signaling. Exp. Hematol. 39, 214–224.e1 (2011).
Zhou, J. et al. Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells. Cell. Signal. 28, 838–849 (2016).
Su, Q. et al. Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer. Oncogene 36, 618–627 (2017).
Kwon, O. J. et al. Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J. Clin. Invest. 126, 2626–2641 (2016).
Liang, S. C. et al. IL-22 induces an acute-phase response. J. Immunol. 185, 5531–5538 (2010).
Sestito, R. et al. STAT3-dependent effects of IL-22 in human keratinocytes are counterregulated by sirtuin 1 through a direct inhibition of STAT3 acetylation. FASEB J. 25, 916–927 (2011).
Beloribi-Djefaflia, S., Vasseur, S. & Guillaumond, F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 5, e189 (2016).
Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).
Mukherjee, A., Kenny, H. A. & Lengyel, E. Unsaturated fatty acids maintain cancer cell stemness. Cell Stem Cell 20, 291–292 (2017).
Rohrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).
Daquinag, A. C. et al. Fatty acid mobilization from adipose tissue is mediated by CD36 posttranslational modifications and intracellular trafficking. JCI Insight 6, e147057 (2021).
Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013).
Balaban, S., Lee, L. S., Schreuder, M. & Hoy, A. J. Obesity and cancer progression: is there a role of fatty acid metabolism. Biomed. Res. Int. 2015, 274585 (2015).
Deep, G. & Schlaepfer, I. R. Aberrant lipid metabolism promotes prostate cancer: role in cell survival under hypoxia and extracellular vesicles biogenesis. Int. J. Mol. Sci. 17, 1061 (2016).
Zaidi, N. et al. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog. Lipid Res. 52, 585–589 (2013).
Ros, S. et al. Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival. Cancer Discov. 2, 328–343 (2012).
Pandey, P. R., Liu, W., Xing, F., Fukuda, K. & Watabe, K. Anti-cancer drugs targeting fatty acid synthase (FAS). Recent Pat. Anticancer Drug Discov. 7, 185–197 (2012).
Kuemmerle, N. B. et al. Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol. Cancer Ther. 10, 427–436 (2011).
Yao, C. H. et al. Exogenous fatty acids are the preferred source of membrane lipids in proliferating fibroblasts. Cell Chem. Biol. 23, 483–493 (2016).
Louie, S. M., Roberts, L. S., Mulvihill, M. M., Luo, K. & Nomura, D. K. Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids. Biochim. Biophys. Acta 1831, 1566–1572 (2013).
Nath, A., Li, I., Roberts, L. R. & Chan, C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci. Rep. 5, 14752 (2015).
Byon, C. H. et al. Free fatty acids enhance breast cancer cell migration through plasminogen activator inhibitor-1 and SMAD4. Lab. Invest. 89, 1221–1228 (2009).
Dalmau, N., Jaumot, J., Tauler, R. & Bedia, C. Epithelial-to-mesenchymal transition involves triacylglycerol accumulation in DU145 prostate cancer cells. Mol. Biosyst. 11, 3397–3406 (2015).
Sanchez-Martinez, R. et al. A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy. Oncotarget 6, 38719–38736 (2015).
Wendt, M. K., Balanis, N., Carlin, C. R. & Schiemann, W. P. STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT 3, e28975 (2014).
Yuan, J., Zhang, F. & Niu, R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci. Rep. 5, 17663 (2015).
Grivennikov, S. I. & Karin, M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21, 11–19 (2010).
Goktuna, S. I., Diamanti, M. A. & Chau, T. L. IKKs and tumor cell plasticity. FEBS J. 285, 2161–2181 (2018).
Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).
Ducharme, N. A. & Bickel, P. E. Lipid droplets in lipogenesis and lipolysis. Endocrinology 149, 942–949 (2008).
Granneman, J. G. & Moore, H. P. Location, location: protein trafficking and lipolysis in adipocytes. Trends Endocrinol. Metab. 19, 3–9 (2008).
Wang, Y. Y. et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2, e87489 (2017).
Arner, P. & Langin, D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol. Metab. 25, 255–262 (2014).
Rohm, M. et al. An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat. Med. 22, 1120–1130 (2016).
Okumura, T. et al. Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells. Oncotarget 8, 18280–18295 (2017).
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).
Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011).
Ye, H. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 19, 23–37 (2016).
Dirat, B. et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 71, 2455–2465 (2011).
Balaban, S. et al. Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab. 5, 1 (2017).
Wen, Y. A. et al. Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis. 8, e2593 (2017).
Chou, C. C. et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 74, 4783–4795 (2014).
Su, F. et al. Progression of prostate carcinoma is promoted by adipose stromal cell-secreted CXCL12 signaling in prostate epithelium. NPJ Precis. Oncol. 5, 26 (2021).
Mele, V. et al. Mesenchymal stromal cells induce epithelial-to-mesenchymal transition in human colorectal cancer cells through the expression of surface-bound TGF-β. Int. J. Cancer 134, 2583–2594 (2014).
Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).
Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).
Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).
Liu, Q. et al. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 31, 61–71 (2016).
Bendre, M. S. et al. Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone 33, 28–37 (2003).
Palafox, M. et al. RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 72, 2879–2888 (2012).
Chu, G. C. et al. RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocr. Relat. Cancer 21, 311–326 (2014).
Li, X. et al. Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. Oncol. Rep. 32, 2605–2611 (2014).
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Yang, P., Hu, Y. & Zhou, Q. The CXCL12-CXCR4 signaling axis plays a key role in cancer metastasis and is a potential target for developing novel therapeutics against metastatic cancer. Curr. Med. Chem. 27, 5543–5561 (2020).
Liotti, A. et al. Periprostatic adipose tissue promotes prostate cancer resistance to docetaxel by paracrine IGF-1 upregulation of TUBB2B β-tubulin isoform. Prostate 81, 407–417 (2021).
Incio, J. et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 6, 852–869 (2016).
Germain, N. et al. Lipid metabolism and resistance to anticancer treatment. Biology 9, 474 (2020).
Yu, X. H., Ren, X. H., Liang, X. H. & Tang, Y. L. Roles of fatty acid metabolism in tumourigenesis: beyond providing nutrition (Review). Mol. Med. Rep. 18, 5307–5316 (2018).
Laurent, V. et al. Periprostatic adipose tissue favors prostate cancer cell invasion in an obesity-dependent manner: role of oxidative stress. Mol. Cancer Res. 17, 821–835 (2019).
Cao, Y. Adipocyte and lipid metabolism in cancer drug resistance. J. Clin. Invest. 129, 3006–3017 (2019).
Wang, T. et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 27, 1357 (2018).
Su, F. et al. Ablation of stromal cells with a targeted proapoptotic peptide suppresses cancer chemotherapy resistance and metastasis. Mol. Ther. Oncolytics 18, 579–586 (2020).
Dong, L., Zieren, R. C., Xue, W., de Reijke, T. M. & Pienta, K. J. Metastatic prostate cancer remains incurable, why? Asian J. Urol. 6, 26–41 (2019).
Gandaglia, G. et al. Distribution of metastatic sites in patients with prostate cancer: a population-based analysis. Prostate 74, 210–216 (2014).
Hernandez, M., Shin, S., Muller, C. & Attane, C. The role of bone marrow adipocytes in cancer progression: the impact of obesity. Cancer Metastasis Rev. 41, 589–605 (2022).
Diedrich, J. D. et al. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget 7, 64854–64877 (2016).
Jiao, S. et al. Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell 179, 1177–1190.e13 (2019).
Nicholson, L. T. & Fong, L. Immune checkpoint inhibition in prostate cancer. Trends Cancer 6, 174–177 (2020).
Daquinag, A. C., Zhang, Y., Amaya-Manzanares, F., Simmons, P. J. & Kolonin, M. G. An isoform of decorin is a resistin receptor on the surface of adipose progenitor cells. Cell Stem Cell 9, 74–86 (2011).
Daquinag, A. C. et al. Targeted proapoptotic peptides depleting adipose stromal cells inhibit tumor growth. Mol. Ther. 24, 34–40 (2016).
Hoda, M. R., Theil, G., Mohammed, N., Fischer, K. & Fornara, P. The adipocyte-derived hormone leptin has proliferative actions on androgen-resistant prostate cancer cells linking obesity to advanced stages of prostate cancer. J. Oncol. 2012, 280386 (2012).
Saglam, K., Aydur, E., Yilmaz, M. & Goktas, S. Leptin influences cellular differentiation and progression in prostate cancer. J. Urol. 169, 1308–1311 (2003).
Stattin, P. et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J. Clin. Endocrinol. Metab. 86, 1341–1345 (2001).
Hsing, A. W. et al. Prostate cancer risk and serum levels of insulin and leptin: a population-based study. J. Natl Cancer Inst. 93, 783–789 (2001).
Mistry, T., Digby, J. E., Desai, K. M. & Randeva, H. S. Leptin and adiponectin interact in the regulation of prostate cancer cell growth via modulation of p53 and bcl-2 expression. BJU Int. 101, 1317–1322 (2008).
Byrne, A. M., Bouchier-Hayes, D. J. & Harmey, J. H. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J. Cell. Mol. Med. 9, 777–794 (2005).
Shibuya, M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem. 153, 13–19 (2013).
Park, J. et al. VEGF-A-Expressing adipose tissue shows rapid beiging and enhanced survival after transplantation and confers IL-4-independent metabolic improvements. Diabetes 66, 1479–1490 (2017).
Nauta, A. et al. Adipose-derived stromal cells overexpressing vascular endothelial growth factor accelerate mouse excisional wound healing. Mol. Ther. 21, 445–455 (2013).
Chen, J. et al. C-reactive protein can upregulate VEGF expression to promote ADSC-induced angiogenesis by activating HIF-1α via CD64/PI3k/Akt and MAPK/ERK signaling pathways. Stem Cell Res. Ther. 7, 114 (2016).
Loskutoff, D. J., van Mourik, J. A., Erickson, L. A. & Lawrence, D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc. Natl Acad. Sci. USA 80, 2956–2960 (1983).
Bastelica, D. et al. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat evidence of differences between visceral and subcutaneous deposits. Arterioscler. Thromb. Vasc. Biol. 22, 173–178 (2002).
Crandall, D. L., Groeling, T. M., Busler, D. E. & Antrilli, T. M. Release of PAI-1 by human preadipocytes and adipocytes independent of insulin and IGF-1. Biochem. Biophys. Res. Commun. 279, 984–988 (2000).
Kubala, M. H. et al. Plasminogen activator inhibitor-1 promotes the recruitment and polarization of macrophages in cancer. Cell Rep. 25, 2177–2191.e7 (2018).
Loppnow, H. & Libby, P. Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1. Cell. Immunol. 122, 493–503 (1989).
Mohamed-Ali, V. et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J. Clin. Endocrinol. Metab. 82, 4196–4200 (1997).
Mi, F. & Gong, L. Secretion of interleukin-6 by bone marrow mesenchymal stem cells promotes metastasis in hepatocellular carcinoma. Biosci. Rep. 37, BSR20170181 (2017).
Lou, W., Ni, Z., Dyer, K., Tweardy, D. J. & Gao, A. C. Interleukin-6 induces prostate cancer cell growth accompanied by activation of stat3 signaling pathway. Prostate 42, 239–242 (2000).
Lee, S. O. et al. Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin. Cancer Res. 9, 370–376 (2003).
Wegiel, B., Bjartell, A., Culig, Z. & Persson, J. L. Interleukin-6 activates PI3K/Akt pathway and regulates cyclin A1 to promote prostate cancer cell survival. Int. J. Cancer 122, 1521–1529 (2008).
Hobisch, A. et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 58, 4640–4645 (1998).
Michalaki, V., Syrigos, K., Charles, P. & Waxman, J. Serum levels of IL-6 and TNF-α correlate with clinicopathological features and patient survival in patients with prostate cancer. Br. J. Cancer 90, 2312–2316 (2004).
Agbanoma, G. et al. Production of TNF-α in macrophages activated by T cells, compared with lipopolysaccharide, uses distinct IL-10-dependent regulatory mechanism. J. Immunol. 188, 1307–1317 (2012).
Wang, R., Jaw, J. J., Stutzman, N. C., Zou, Z. & Sun, P. D. Natural killer cell-produced IFN-γ and TNF-α induce target cell cytolysis through up-regulation of ICAM-1. J. Leukoc. Biol. 91, 299–309 (2012).
Nakashima, J. et al. Association between tumor necrosis factor in serum and cachexia in patients with prostate cancer. Clin. Cancer Res. 4, 1743–1748 (1998).
Wang, N. et al. CXCL1 derived from tumor-associated macrophages promotes breast cancer metastasis via activating NF-κB/SOX4 signaling. Cell Death Dis. 9, 880 (2018).
Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).
Wang, D. et al. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J. Exp. Med. 203, 941–951 (2006).
Miyake, M., Goodison, S., Urquidi, V., Gomes Giacoia, E. & Rosser, C. J. Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways. Lab. Invest. 93, 768–778 (2013).
Lu, Y. et al. CXCL1-LCN2 paracrine axis promotes progression of prostate cancer via the Src activation and epithelial-mesenchymal transition. Cell Commun. Signal. 17, 118 (2019).
Kuo, P. L., Shen, K. H., Hung, S. H. & Hsu, Y. L. CXCL1/GROα increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-κB/HDAC1 epigenetic regulation. Carcinogenesis 33, 2477–2487 (2012).
Chavey, C. et al. CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance. Cell Metab. 9, 339–349 (2009).
Begley, L. A. et al. CXCL5 promotes prostate cancer progression. Neoplasia 10, 244–254 (2008).
Qi, Y. et al. High C-X-C motif chemokine 5 expression is associated with malignant phenotypes of prostate cancer cells via autocrine and paracrine pathways. Int. J. Oncol. 53, 358–370 (2018).
Kuo, P. L., Chen, Y. H., Chen, T. C., Shen, K. H. & Hsu, Y. L. CXCL5/ENA78 increased cell migration and epithelial-to-mesenchymal transition of hormone-independent prostate cancer by early growth response-1/snail signaling pathway. J. Cell Physiol. 226, 1224–1231 (2011).
Hattermann, K. & Mentlein, R. An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Ann. Anat. 195, 103–110 (2013).
Conley-LaComb, M. K. et al. PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol. Cancer 12, 85 (2013).
Rivat, C. et al. Src family kinases involved in CXCL12-induced loss of acute morphine analgesia. Brain Behav. Immun. 38, 38–52 (2014).
Duda, D. G. et al. CXCL12 (SDF1α)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin. Cancer Res. 17, 2074–2080 (2011).
Ammirante, M., Shalapour, S., Kang, Y., Jamieson, C. A. & Karin, M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc. Natl Acad. Sci. USA 111, 14776–14781 (2014).
Kusuyama, J. et al. CXCL13 is a differentiation- and hypoxia-induced adipocytokine that exacerbates the inflammatory phenotype of adipocytes through PHLPP1 induction. Biochem. J. 476, 3533–3548 (2019).
Kabir, S. M., Lee, E. S. & Son, D. S. Chemokine network during adipogenesis in 3T3-L1 cells: differential response between growth and proinflammatory factor in preadipocytes vs. adipocytes. Adipocyte 3, 97–106 (2014).
El-Haibi, C. P. et al. Antibody microarray analysis of signaling networks regulated by Cxcl13 and Cxcr5 in prostate cancer. J. Proteomics Bioinform. 5, 177–184 (2012).
Deng, L., Chen, N., Li, Y., Zheng, H. & Lei, Q. CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim. Biophys. Acta 1806, 42–49 (2010).
Hu, W. et al. CXCR6 is expressed in human prostate cancer in vivo and is involved in the in vitro invasion of PC3 and LNCap cells. Cancer Sci. 99, 1362–1369 (2008).
Wang, J. et al. CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway. Cancer Res. 68, 10367–10376 (2008).
Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).
Sartipy, P. & Loskutoff, D. J. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 100, 7265–7270 (2003).
Li, X. et al. A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res. 69, 1685–1692 (2009).
Loberg, R. D. et al. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia 9, 556–562 (2007).
Natsagdorj, A. et al. CCL2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells. Cancer Sci. 110, 279–288 (2019).
Loberg, R. D. et al. CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia 8, 578–586 (2006).
Roca, H., Varsos, Z. S., Mizutani, K. & Pienta, K. J. CCL2, survivin and autophagy: new links with implications in human cancer. Autophagy 4, 969–971 (2008).
van Golen, K. L. et al. CCL2 induces prostate cancer transendothelial cell migration via activation of the small GTPase Rac. J. Cell Biochem. 104, 1587–1597 (2008).
Danforth, J. M. et al. Macrophage inflammatory protein-1 α expression in vivo and in vitro: the role of lipoteichoic acid. Clin. Immunol. Immunopathol. 74, 77–83 (1995).
Menten, P., Wuyts, A. & Van Damme, J. Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 13, 455–481 (2002).
Berkman, N. et al. Corticosteroid inhibition of macrophage inflammatory protein-1 α in human monocytes and alveolar macrophages. Am. J. Physiol. 269, L443–L452 (1995).
Sherry, B. et al. Nitric oxide regulates MIP-1α expression in primary macrophages and T lymphocytes: implications for anti-HIV-1 response. Mol. Med. 6, 542–549 (2000).
Yang, S. K., Eckmann, L., Panja, A. & Kagnoff, M. F. Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology 113, 1214–1223 (1997).
Surmi, B. K., Webb, C. D., Ristau, A. C. & Hasty, A. H. Absence of macrophage inflammatory protein-1α does not impact macrophage accumulation in adipose tissue of diet-induced obese mice. Am. J. Physiol. Endocrinol. Metab. 299, E437–E445 (2010).
Dang, T. & Liou, G. Y. Macrophage cytokines enhance cell proliferation of normal prostate epithelial cells through activation of ERK and Akt. Sci. Rep. 8, 7718 (2018).
Maurer, M. & von Stebut, E. Macrophage inflammatory protein-1. Int. J. Biochem. Cell Biol. 36, 1882–1886 (2004).
Ziegler, S. F., Tough, T. W., Franklin, T. L., Armitage, R. J. & Alderson, M. R. Induction of macrophage inflammatory protein-1 β gene expression in human monocytes by lipopolysaccharide and IL-7. J. Immunol. 147, 2234–2239 (1991).
Kim, J. J. et al. Intracellular adhesion molecule-1 modulates β-chemokines and directly costimulates T cells in vivo. J. Clin. Invest. 103, 869–877 (1999).
Krzysiek, R. et al. Antigen receptor engagement selectively induces macrophage inflammatory protein-1 α (MIP-1 α) and MIP-1 β chemokine production in human B cells. J. Immunol. 162, 4455–4463 (1999).
Lapinet, J. A., Scapini, P., Calzetti, F., Perez, O. & Cassatella, M. A. Gene expression and production of tumor necrosis factor α, interleukin-1β (IL-1β), IL-8, macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and γ interferon-inducible protein 10 by human neutrophils stimulated with group B meningococcal outer membrane vesicles. Infect. Immun. 68, 6917–6923 (2000).
Shukaliak, J. A. & Dorovini-Zis, K. Expression of the β-chemokines RANTES and MIP-1 β by human brain microvessel endothelial cells in primary culture. J. Neuropathol. Exp. Neurol. 59, 339–352 (2000).
Cocchi, F. et al. Identification of RANTES, MIP-1 α, and MIP-1 β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815 (1995).
Aldinucci, D. & Colombatti, A. The inflammatory chemokine CCL5 and cancer progression. Mediators Inflamm. 2014, 292376 (2014).
Vaday, G. G., Peehl, D. M., Kadam, P. A. & Lawrence, D. M. Expression of CCL5 (RANTES) and CCR5 in prostate cancer. Prostate 66, 124–134 (2006).
Huang, R. et al. CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling. Cell Death Dis. 11, 234 (2020).
Lee, Y. S. et al. Crosstalk between CCL7 and CCR3 promotes metastasis of colon cancer cells via ERK-JNK signaling pathways. Oncotarget 7, 36842–36853 (2016).
Liu, J. et al. Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways. Cancer Lett. 379, 49–59 (2016).
She, S. et al. Functional roles of chemokine receptor CCR2 and its ligands in liver disease. Front. Immunol. 13, 812431 (2022).
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This work was supported in part by NIH grants R01 CA196259 (to J.D. and M.G.K.).
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Saha, A., Kolonin, M.G. & DiGiovanni, J. Obesity and prostate cancer — microenvironmental roles of adipose tissue. Nat Rev Urol 20, 579–596 (2023). https://doi.org/10.1038/s41585-023-00764-9
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DOI: https://doi.org/10.1038/s41585-023-00764-9
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