The chemokine system,and its CCR5 and CXCR4 receptors,as potential targets for personalized therapy in cancer

Chemokines and their receptors regulate the trafficking of leukocytes in hematopoiesis and inflammation, and thus are fundamental to the immune integrity of the host. In parallel, members of the chemokine system exert a large variety of functions that dictate processes of cancer development and progression. Chemokines can act as pro-tumoral or anti-tumoral regulators of malignancy by affecting cells of the tumor microenvironment (leukocytes, endothelial cells, fibroblasts) and the tumor cells themselves (migration, invasion, proliferation, resistance to chemotherapy). Several of the chemokines are generally skewed towards the cancer-promoting direction, including primarily the CCR5–CCL5 (RANTES) and the CXCR4–CXCL12 (SDF-1) axes. This review provides a general view of chemokines and chemokine receptors as regulators of malignancy, describing their multi-faceted activities in cancer. The tumor-promoting activities of the CCR5–CCL5 and CXCR4–CXCL12 pathways are enlightened, emphasizing their potential use as targets for personalized therapy. Indeed, novel blockers of chemokines and their receptors are constantly emerging, and two chemokine receptor inhibitors were recently approved for clinical use: Maraviroc for CCR5 and Plerixafor for CXCR4. The review addresses ongoing pre-clinical and clinical trials using these modalities and others in cancer. Then, challenges and opportunities of personalized therapy directed against chemokines and their receptors in malignancy are discussed, demonstrating that such novel personalized cancer therapies hold many challenges, but also offer hope for cancer patients.