How does obesity promote breast cancer tumor growth?

Obesity is a risk factor for many cancers. Maguire et al., 2021Maguire O.A. Ackerman S.E. Szwed S.K. Maganti A.V. Marchildon F. Huang X. Kramer D.J. Rosas-Villegas A. Gelfer R.G. Turner L.E. et al.Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.Cell Metab. 2021; 33 (this issue): 499-512Abstract Full Text Full Text PDF Scopus (11) Google Scholar found increased creatine synthesis by the adipocytes adjacent to breast cancers in obese mice. The creatine is transported into the cancer cells, producing larger tumors, possibly due to greater energy availability. Obesity is a risk factor for many cancers. Maguire et al., 2021Maguire O.A. Ackerman S.E. Szwed S.K. Maganti A.V. Marchildon F. Huang X. Kramer D.J. Rosas-Villegas A. Gelfer R.G. Turner L.E. et al.Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.Cell Metab. 2021; 33 (this issue): 499-512Abstract Full Text Full Text PDF Scopus (11) Google Scholar found increased creatine synthesis by the adipocytes adjacent to breast cancers in obese mice. The creatine is transported into the cancer cells, producing larger tumors, possibly due to greater energy availability. Obesity is associated with an increased risk of many types of cancer (breast, uterus, ovary, esophagus, stomach, colon/rectum, liver, gallbladder, pancreas, kidney, thyroid, meninges, and multiple myeloma) (Lauby-Secretan et al., 2016Lauby-Secretan B. Scoccianti C. Loomis D. Grosse Y. Bianchini F. Straif K. International Agency for Research on Cancer Handbook Working GroupBody fatness and cancer--viewpoint of the IARC Working Group.N. Engl. J. Med. 2016; 375: 794-798Crossref PubMed Scopus (1242) Google Scholar). These epidemiology data are supported by the observation that the risk of breast cancer is lower after bariatric weight-loss surgery. In contrast to the well-studied role of obesity in metabolic disease, the mechanisms whereby obesity contributes to cancer are poorly understood. In this issue, Maguire et al., 2021Maguire O.A. Ackerman S.E. Szwed S.K. Maganti A.V. Marchildon F. Huang X. Kramer D.J. Rosas-Villegas A. Gelfer R.G. Turner L.E. et al.Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.Cell Metab. 2021; 33 (this issue): 499-512Abstract Full Text Full Text PDF Scopus (11) Google Scholar produced tumors by implantation of syngeneic breast cancer E0771 cells in mice. Larger tumors grew in diet-induced obese, compared to lean, mice. A pair-feeding experiment suggested that the enhanced tumor growth was due to the obesity per se, not a particular dietary component. mRNA profiling of peritumoral (compared to contralateral) adipose tissue revealed increased levels of glycine amidinotransferase (Gatm) mRNA, encoding the rate-limiting enzyme in creatine biosynthesis. Obese mice with adipose-specific knockout of Gatm had reduced tumor volumes and increased survival. Next, the authors showed that the previously identified creatine transporter, Slc6a8, is the transporter in E0771 cells. Implantation of E0771 cells in which Slc6a8 expression was knocked down produced smaller tumors. These data all support a model whereby peritumoral adipocytes in obese mice synthesize more creatine, which is transported into nearby cancer cells, promoting tumor growth. Creatine is obtained both from the diet and by endogenous synthesis (Wyss and Kaddurah-Daouk, 2000Wyss M. Kaddurah-Daouk R. Creatine and creatinine metabolism.Physiol. Rev. 2000; 80: 1107-1213Crossref PubMed Scopus (1757) Google Scholar). Gatm RNA levels, indicating sites of creatine synthesis, are highest in the kidney, liver (human), exocrine pancreas, and certain immune cells, with expression also in other tissues. The canonical function of creatine is to fuel a high-energy phosphate reservoir, with phosphocreatine maintaining the high ATP:ADP ratio. Creatine phosphorylation is catalyzed by four creatine kinases, which have different tissue and subcellular distributions. The E0771 tumors in the obese mice have higher creatine and phosphocreatine content, so a plausible explanation for these larger tumors is an increased cell energy supply, promoting cell growth. This is consistent with the observation that mitochondrial creatine kinase is stabilized in HER2+ breast cancer cells (overexpressing HER2, human epidermal growth factor receptor 2), increasing cytosolic phosphocreatine and thus cytosolic energy supply (Kurmi et al., 2018Kurmi K. Hitosugi S. Yu J. Boakye-Agyeman F. Wiese E.K. Larson T.R. Dai Q. Machida Y.J. Lou Z. Wang L. et al.Tyrosine phosphorylation of mitochondrial creatine kinase 1 enhances a druggable tumor energy shuttle pathway.Cell Metab. 2018; 28: 833-847.e8Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Roles for creatine and/or creatine kinase are also suggested in T cell development, macrophage polarization away from the pro-inflammatory M1 class, and thermogenic adipose tissue (Kazak and Cohen, 2020Kazak L. Cohen P. Creatine metabolism: energy homeostasis, immunity and cancer biology.Nat. Rev. Endocrinol. 2020; 16: 421-436Crossref PubMed Scopus (32) Google Scholar). In addition to their investigation of peritumoral tissue, Maguire et al., 2021Maguire O.A. Ackerman S.E. Szwed S.K. Maganti A.V. Marchildon F. Huang X. Kramer D.J. Rosas-Villegas A. Gelfer R.G. Turner L.E. et al.Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.Cell Metab. 2021; 33 (this issue): 499-512Abstract Full Text Full Text PDF Scopus (11) Google Scholar) also used mRNA profiling to identify obesity-dependent gene expression variation in the tumors themselves. A specific fatty acyl-CoA synthase, Acsbg1, was highly upregulated, although its knockdown did not decrease tumor volume. The mechanism(s) by which E0771 tumors cause peritumoral adipocytes to increase their Gatm mRNA levels are unknown and will be important to elucidate. One possibility for Gatm induction is a binary system, involving only tumor cells and adipocytes. The tumor cells could directly signal the adipocytes by cell-cell contact and/or production of signaling metabolites/hormones. Alternatively, the tumor cells might be affecting non-adipocytes, which secondarily induce adipocyte Gatm. Obese adipose tissue has an increased inflammatory tone, with a different ensemble of cytokines and immune cell populations than lean tissue. Thus, the greater induction of Gatm by peritumoral adipocytes could include contributions by immune or stromovascular cells and might result from changes in extracellular matrix, angiogenesis, oxygenation/redox state, metabolite/nutrient levels, and/or hormone levels (Quail and Dannenberg, 2019Quail D.F. Dannenberg A.J. The obese adipose tissue microenvironment in cancer development and progression.Nat. Rev. Endocrinol. 2019; 15: 139-154Crossref PubMed Scopus (164) Google Scholar). While the transition from non-malignant to breast cancer requires only a handful of mutations, well-established tumors accumulate hundreds or thousands of mutations (Nik-Zainal et al., 2012Nik-Zainal S. Van Loo P. Wedge D.C. Alexandrov L.B. Greenman C.D. Lau K.W. Raine K. Jones D. Marshall J. Ramakrishna M. et al.Breast Cancer Working Group of the International Cancer Genome ConsortiumThe life history of 21 breast cancers.Cell. 2012; 149: 994-1007Abstract Full Text Full Text PDF PubMed Scopus (922) Google Scholar). In contrast, peritumoral host tissue should have few mutations and a stable genome. Thus, the host’s response to a tumor may follow a more stable, defined playbook compared to the tumor’s more variable mRNA expression pattern and biology. It will be important to explore the generality of increased Gatm/creatine production by peritumoral adipocytes. Does implantation of non-E0771 breast cancers also increase Gatm mRNA levels? What about other tumor types and other body sites? This is crucial, as cancer biology exhibits large inter-species differences and anticancer efficacy data obtained in mice often poorly predict response in humans (Mak et al., 2014Mak I.W. Evaniew N. Ghert M. Lost in translation: animal models and clinical trials in cancer treatment.Am. J. Transl. Res. 2014; 6: 114-118PubMed Google Scholar). In Maguire et al., 2021Maguire O.A. Ackerman S.E. Szwed S.K. Maganti A.V. Marchildon F. Huang X. Kramer D.J. Rosas-Villegas A. Gelfer R.G. Turner L.E. et al.Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.Cell Metab. 2021; 33 (this issue): 499-512Abstract Full Text Full Text PDF Scopus (11) Google Scholar, the host-derived creatine accelerated tumor growth, a bad thing for the host. However, if increased peritumoral creatine is a general host response, it might also signal or drive beneficial processes. Indeed, the Slc6a8 creatine transporter is required for full function of tumor-infiltrating immune cells, which counters tumor growth (Di Biase et al., 2019Di Biase S. Ma X. Wang X. Yu J. Wang Y.C. Smith D.J. Zhou Y. Li Z. Kim Y.J. Clarke N. et al.Creatine uptake regulates CD8 T cell antitumor immunity.J. Exp. Med. 2019; 216: 2869-2882Crossref PubMed Scopus (32) Google Scholar). If increased creatine production is a conserved response, what other host physiology and adaptive responses does creatine trigger or facilitate? Interestingly, creatine is very widely available as a nutritional supplement (Kreider et al., 2017Kreider R.B. Kalman D.S. Antonio J. Ziegenfuss T.N. Wildman R. Collins R. Candow D.G. Kleiner S.M. Almada A.L. Lopez H.L. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine.J. Int. Soc. Sports Nutr. 2017; 14: 18Crossref PubMed Scopus (203) Google Scholar). It is commonly used in combination with resistance training to increase muscle strength and mass. There are also numerous other indications where creatine supplementation has been explored or proposed. While the human studies are of limited power to detect rare events, no adverse safety signal has been detected. In human breast cancer samples, both ACSBG1 and SLC6A8 RNA levels were associated with tumor grade. In triple-negative breast cancers (the ∼20% of breast cancers that do not express estrogen or progesterone receptors and do not overexpress HER2), high SLC6A8 expression was associated with worse prognosis. There is already a wealth of information on germline and somatic mutations and RNA expression patterns in breast cancer. The reproducibility and prognostic and therapeutic utilities of ACSBG1 and SLC6A8 RNA level changes will need to be evaluated prospectively in the management of the different types and stages of breast cancer. We thank Oksana Gavrilova for helpful comments. The author is supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The author declares no competing interests. Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancerMaguire et al.Cell MetabolismFebruary 16, 2021In BriefObesity is a major risk factor for adverse outcomes in breast cancer. Maguire, Ackerman et al. reveal Gatm and Acsbg1 as molecular regulators of obesity-driven breast cancer progression. They further show that in obesity creatine is a key metabolite in the crosstalk between adipocytes and breast tumors. Full-Text PDF