Endocrine Abstracts

Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (e.g. breast cancers and ovarian metastasis to omentum). Adipose tissue in obesity and tumour micro-environmentsshare a common pathogenic feature, oxygen deprivation (hypoxia, Hx). Here we hypothesised that this hypoxic microenvironment causes changes in key metabolic pathways in adipocytes leading to increased cancer cell growth. To test this, human or mouse breast (BC) and ovarian cancer (OvCa) cell lines were co-cultured with human or mouse adipocytes respectively under hypoxia (0.5% O_2,24h) to resemble a tumour environment. Hypoxic cancer-conditioned media (CCM) increased lipolysis in both human and mouse adipocytes (i.e. non-esterified fatty acid release in Hx: human adipocytes with CCM vs adipocytes alone, 2.5-fold increase, P < 0.001). This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on the hypoxia inducible factor, HIF1α, expression in adipocytes, as adipocytes lacking HIF1α (Hif1αKO^ad) showed a blunted lipolytic responses under hypoxic conditions. Proliferation of cancer cells was also suppressed after co-culture with Hif1αKO^ad adipocytes (AUC proliferation assay for BC cells+control adipocytes vs BC cells+Hif1αKO^ad adipocytes; 116 vs 70, P < 0.01). To address whether metabolic changes driven by hypoxia in adipocytes can induce proliferation even in non-malignant cells, we performed LC/MS targeted metabolomics in the media of human Simpson-Golabi-Behmel Syndrome (SGBS) adipocytes after co-culture with MCF10A breast epithelial cells. Hx depleted glucose and increased lactate, pyruvate and ribose-5-phosphate levels in SGBS adipocytes. These re-programmed adipocytes increased proliferation of even the non-malignant cells (AUC proliferation assay for MCF10A in Hx; MCF10A alone vs MCF10A+SGBS, 188 vs 446, P < 0.01). Hypoxia re-programmes adipocyte metabolism, providing energy substrates for cancer cell proliferation and represents a key link between obesity and increased cancer risk.