{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:13:10Z","timestamp":1787026390620,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC\/MS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1\u03b1 expression in adipocytes, as mouse adipocytes lacking HIF1\u03b1 showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Here, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2022.989523","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T02:34:58Z","timestamp":1666060498000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation"],"prefix":"10.3389","volume":"13","author":[{"given":"R.","family":"Aird","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Wills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. F.","family":"Roby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"B\u00e9n\u00e9zech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. H.","family":"Stimson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Wabitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. W.","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Finch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Michailidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/S0140-6736(08)60269-X","article-title":"Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies","volume":"371","author":"Renehan","year":"2008","journal-title":"Lancet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/nrendo.2014.94","article-title":"Obesity and cancer\u2013mechanisms underlying tumour progression and recurrence","volume":"10","author":"Park","year":"2014","journal-title":"Nat Rev Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1038\/nm.2492","article-title":"Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth","volume":"17","author":"Nieman","year":"2011","journal-title":"Nat Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e87489","DOI":"10.1172\/jci.insight.87489","article-title":"Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells","volume":"2","author":"Wang","year":"2017","journal-title":"JCI Insight"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e102525","DOI":"10.15252\/embj.2019102525","article-title":"Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells","volume":"39","author":"Clement","year":"2020","journal-title":"EMBO J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5874","DOI":"10.1073\/pnas.1200447109","article-title":"Scherer PE dichotomous effects of VEGF-a on adipose tissue dysfunction","volume":"109","author":"Sun","year":"2012","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B7","doi-asserted-by":"publisher","first-page":"4188","DOI":"10.1074\/jbc.M111.259325","article-title":"Increased angiogenesis protects against adipose hypoxia and fibrosis in metabolic disease-resistant 11\u03b2-hydroxysteroid dehydrogenase type 1 (HSD1)-deficient mice","volume":"287","author":"Michailidou","year":"2012","journal-title":"J Biol Chem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.2337\/db11-0832","article-title":"Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance","volume":"61","author":"Elias","year":"2012","journal-title":"Diabetes."},{"key":"B9","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1111\/joim.12091","article-title":"Tumour oxygenation: implications for breast cancer prognosis","volume":"274","author":"Rundqvist","year":"2013","journal-title":"J Intern Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1161\/ATVBAHA.110.214106","article-title":"From vessel sprouting to normalization: Role of the prolyl hydroxylase domain protein\/hypoxia-inducible factor oxygen-sensing machinery","volume":"30","author":"Coulon","year":"2010","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nrc704","article-title":"Hypoxia-a key regulatory factor in tumour growth","volume":"2","author":"Harris","year":"2002","journal-title":"Nat Rev Cancer."},{"key":"B12","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cophys.2019.09.005","article-title":"Fundamental roles of hypoxia signalling in metabolism and inflammation in obesity and beyond","volume":"2","author":"Michailidou","year":"2019","journal-title":"Curr Opin Physiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1172\/JCI64993","article-title":"Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis","volume":"123","author":"Chaturvedi","year":"2013","journal-title":"J Clin Invest."},{"key":"B14","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1038\/s41568-021-00388-4","article-title":"Tumour fatty acid metabolism in the context of therapy resistance and obesity","volume":"21","author":"Hoy","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.celrep.2014.08.056","article-title":"Fatty acid uptake and lipid storage induced by HIF-1\u03b1 contribute to cell growth and survival after hypoxia-reoxygenation","volume":"9","author":"Bensaad","year":"2014","journal-title":"Cell Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/2049-3002-1-3","article-title":"Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth","volume":"1","author":"Griffiths","year":"2013","journal-title":"Cancer Metab"},{"key":"B17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nature20791","article-title":"Targeting metastasis-initiating cells through the fatty acid receptor CD36","volume":"541","author":"Pascual","year":"2017","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40170-016-0163-7","article-title":"Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration","volume":"5","author":"Balaban","year":"2017","journal-title":"Cancer Metab"},{"key":"B19","doi-asserted-by":"publisher","first-page":"733","DOI":"10.2337\/db14-0233","article-title":"Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion","volume":"64","author":"Michailidou","year":"2015","journal-title":"Diabetes."},{"key":"B20","article-title":"Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth","volume":"60","author":"Ryan","year":"2000","journal-title":"Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"15712","DOI":"10.1073\/pnas.2536828100","article-title":"Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle","volume":"100","author":"He","year":"2003","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B22","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/sj.ijo.0801520","article-title":"Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation","volume":"25","author":"Wabitsch","year":"2001","journal-title":"Int J Obes Relat Metab Disord"},{"key":"B23","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1093\/carcin\/21.4.585","article-title":"Development of a syngeneic mouse model for events related to ovarian cancer","volume":"21","author":"Roby","year":"2000","journal-title":"Carcinogenesis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/nature10138","article-title":"CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis","volume":"475","author":"Qian","year":"2011","journal-title":"Nature."},{"key":"B25","doi-asserted-by":"publisher","first-page":"9616","DOI":"10.1021\/acs.analchem.7b02401","article-title":"AssayR: A simple mass spectrometry software tool for targeted metabolimic and stable isotope tracer analyses","volume":"89","author":"Willis","year":"2017","journal-title":"Anal Chem"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e0162167","DOI":"10.1371\/journal.pone.0162167","article-title":"Regulation of lipolysis and adipose tissue signaling during acute endotoxin-induced inflammation: A human randomized crossover trial","volume":"11","author":"Rittig","year":"2016","journal-title":"PloS One"},{"key":"B27","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/28867","article-title":"Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis","volume":"394","author":"Carmeliet","year":"1998","journal-title":"Nature."},{"key":"B28","doi-asserted-by":"publisher","first-page":"7919","DOI":"10.1074\/jbc.M010189200","article-title":"Hypoxia inhibits G1\/S transition through regulation of p27 expression","volume":"276","author":"Gardner","year":"2001","journal-title":"J Biol Chem"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e46543","DOI":"10.1371\/journal.pone.0046543","article-title":"Hypoxic conditions induce a cancer-like phenotype in human breast epithelial cells","volume":"7","author":"Vaapil","year":"2012","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroplasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3775","DOI":"10.3390\/ijms22073775","article-title":"Triulzi T.Cancer-associated adipocytes in breast cancer: Causes and consequences","volume":"22","author":"Rybinska","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"6487","DOI":"10.1126\/science.aaw5473","article-title":"DeBerardinis RJ.Metabolic reprogramming and cancer progression","volume":"368","author":"Faubert","year":"2020","journal-title":"Science."},{"key":"B33","doi-asserted-by":"publisher","first-page":"19730","DOI":"10.18632\/oncotarget.24808","article-title":"Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia","volume":"9","author":"Danielsson","year":"2018","journal-title":"Oncotarget."},{"key":"B34","doi-asserted-by":"publisher","first-page":"19345","DOI":"10.1073\/pnas.0709747104","article-title":"Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis","volume":"104","author":"DeBerardinis","year":"2007","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B35","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/s1470-2045(03)01179-3","article-title":"Understanding the intersections between metabolism and cancer biology","volume":"168","author":"Vander Heiden","year":"2017","journal-title":"Cell."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307237110","article-title":"Hypoxic and ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids","volume":"110","author":"Kamphorst","year":"2013","journal-title":"Proc Natl Acad Sci USA."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.05.005","article-title":"Cancer lipid metabolism confers antiangiogenic drug resistance","volume":"28","author":"Iwamoto","year":"2018","journal-title":"Cell Metab"},{"key":"B38","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/s1470-2045(03)01179-3","article-title":"Impaired glucose intolerance is linked to cancer","volume":"4","author":"Senior","year":"2003","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.3892\/or.2015.3880","article-title":"Adipocyte hypoxia promotes epithelial-mesenchymal transition-related gene expression and estrogen receptor-negative phenotype in breast cancer cells","volume":"33","author":"Yao-Borengasser","year":"2015","journal-title":"Oncol Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20112142","article-title":"Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity","volume":"445","author":"Frizzell","year":"2012","journal-title":"Biochem J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.06.017","article-title":"HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability","volume":"8","author":"Isaacs","year":"2005","journal-title":"Cancer Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi227","article-title":"Accumulation of Krebs cycle intermediates and over-expression of HIF1\u03b1 in tumours which result from germline FH and SDH mutations","volume":"14","author":"Pollard","year":"2005","journal-title":"Hum Mol Genet"},{"key":"B43","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.cmet.2019.05.005","article-title":"A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate","volume":"30","author":"Wang","year":"2019","journal-title":"Cell Metab"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1002\/ijc.28809","article-title":"Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer","volume":"135","author":"Poff AM Ari","year":"2014","journal-title":"Int J Cancer."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01554","article-title":"Mammary adipose tissue control of breast cancer progression: Impact of obesity and diabetes","volume":"10","author":"D\u2019Esposito","year":"2020","journal-title":"Front Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-022-10059-x","article-title":"The adipocyte microenvironment and cancer","volume":"41","author":"Mukherjee","year":"2022","journal-title":"Cancer Metastasis Rev"},{"key":"B48","doi-asserted-by":"publisher","first-page":"eabj2807","DOI":"10.1126\/scisignal.abj2807","article-title":"Adipocyte-derived exosomes may promote breast cancer progression in type 2 diabetes","volume":"14","author":"Jafari","year":"2021","journal-title":"Sci Signal"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.989523\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T02:35:04Z","timestamp":1666060504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.989523\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,18]]},"references-count":48,"alternative-id":["10.3389\/fendo.2022.989523"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.989523","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,18]]},"article-number":"989523"}}