Cancer-associated fibroblasts and tumor growth--bystanders turning into key players.

Novel mechanisms, and molecular mediators, of the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified. These include CXCL12/SDF-1-mediated recruitment of bone marrow-derived endothelial precursor cell and pro-metastatic effects of CCL5. Co-culture experiments also suggest that CAFs can influence the drug-sensitivity of cancer cells. Comparisons of CAFs from different tumors have started to identify tumor-type specific differences in CAF gene expression and marker protein profiling indicates the existence of multiple distinct co-existing CAF-subsets. Studies in animal models have demonstrated that CAFs can be derived from bone marrow-derived cells or from epithelial or endothelial cells undergoing mesenchymal transition. The genetic status of CAFs remains controversial following conflicting findings. Meanwhile, analyses of CAFs from human tumors have revealed consistent epigenetic changes. An increasing number of translational studies have emphasized the prognostic significance of different CAF-related tumor characteristics. Clinical studies aiming at CAF-targeting can now be envisioned based on findings from experimental intervention studies with agents targeting, for example FAP or PDGF-, TGF-beta- or hedgehog-signaling.