Role of stromal fibroblasts in prostate carcinoma progression and metabolic reprogramming of cancer cells

Cancer-Associated Fibroblasts (CAFs) play a key role in cancer malignancy, eliciting a pro-oxidant environment and endowing cancer cells with invasive motility, stem cell properties, metastatic spread and deeply metabolic alterations. Our aim is to understand the interplay among CAFs, oxidative stress and metabolic reprogramming of prostate cancer (PCa) cells during tumor progression, as well as their possible involvement in drug resistance. We demonstrated a reciprocal metabolic reprogramming of CAFs and PCa cells. In particular, CAFs shift their metabolism towards a more glycolytic one, through a HIF1- and oxidative stress-dependent extrusion of lactate. This catabolite shuttles back to cancer cells, which use it for TCA cycle and protein synthesis, fueling cancer cell proliferation. Furthermore, metabolically reprogrammed CAFs express carbonic anhydrase IX, which is mandatory to elicit the secretion of metalloprotease-2 and -9 through acidification of extracellular milieu, thus driving epithelial-mesenchymal transition in PCa cells. We finally reported the importance of metabolic adaptations during chemoresistance acquisition. Indeed, docetaxel-resistant PCa cells undergo an escape from glycolytic metabolism with a potential involvement of mitochondrial respiration to confer a metabolic advantage to these cells.