Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness.

Although cancer-associated fibroblasts (CAF) are key determinants in the malignant progression of cancer, their functional contribution to this process is still unclear. Analysis of the mutual interplay between prostate carcinoma cells and CAFs revealed a mandatory role of carcinoma-derived interleukin-6 in fibroblast activation. In turn, activated fibroblasts through secretion of metalloproteinases elicit in cancer cells a clear epithelial-mesenchymal transition (EMT), as well as enhancement of tumor growth and development of spontaneous metastases. CAF-induced EMT leads prostate carcinoma cells to enhance expression of stem cell markers, as well as the ability to form prostaspheres and to self-renew. Hence, the paracrine interplay between CAFs and cancer cells leads to an EMT-driven gain of cancer stem cell properties associated with aggressiveness and metastatic spread.