Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy

Cells of the tumor microenvironment play active roles in determining the malignancy phenotype. The host cells and the cancer cells cross-talk via a large variety of soluble factors, whose effects on both partners determine the final outcome of the tumorigenic process. In this review, we focus on the interactions between cancer cells and fibroblasts that are found in their proximity in the growing and progressing tumor and describe the roles of chemokines in mediating such cross-talks. Cancer-associated fibroblasts (CAFs, also termed tumor-associated fibroblasts) were found recently to acquire properties that promote tumor development and metastasis formation, as is also the case for specific members of the chemokine family. In this review, we suggest that there is a bidirectional cross-talk between tumor cells and CAFs, which leads via chemokine activities to increased malignancy. This cross-talk is manifested by the fact that cancer cells release factors that enhance the ability of the fibroblasts to secrete a variety of tumor-promoting chemokines, which then act back on the malignant cells to promote their proliferative, migratory, and invasive properties. The CAF-released chemokines also affect the tumor microenvironment, leading to increased angiogenesis and possibly to an elevated presence of cancer-supporting macrophages in tumors. Here, we describe these bidirectional interactions and the chemokines that are involved in these processes: mainly the CXCL12-CXCR4 pair but also other chemokines, including CCL2, CCL5, CCL7, CXCL8, and CXCL14. The overall findings suggest that chemokines stand at the crossroads of tumor-CAF interactions that lead to increased malignancy in many cancer diseases.