A centralized communication network: Recent insights into the role of the cancer associated fibroblast in the development of drug resistance in tumors

Although cancer cells are located within a microenvironment consisting of immune cells, endothelial cells, fibroblasts and extracellular matrix (ECM), the role of the cancer-associated fibroblasts (CAFs) in driving tumorigenesis is relatively underinvestigated. Recent data suggest that a stiff ECM, generated by CAFs, and associated integrin-dependent signaling underlies the development of drug resistance to BRAF inhibitors in melanoma. Drugs targeting the matricellular protein CCN2 (centralized communication network 2, formerly termed connective tissue growth factor), are in clinical development for cancers; for example, FG-3019, an antibody targeting CCN2 has recently entered Phase III trials for pancreatic cancer. Recent data show that fibroblast-specific production of CCN2, which signals through integrins and whose overexpression in human melanomas is independent of BRAF mutational status, is essential for neovascularization, including vasculogenic mimicry, in melanoma. In clinical melanoma samples, a FAP/ITGA11/COL1A1/CCN2-expressing CAF population negatively correlates with disease-free survival. These data emphasize the essential role for a CCN2-expressing subset of CAFs in cancer progression and suggest that targeting the CAFs in the tumor microenvironment, for example by blocking the action of CCN2, may be useful in combination therapies to treat cancers.