The inflammatory chemokine CCL5 and cancer progression

Abstract

Until recently, inflammatory chemokines were viewed mainly as indispensable "gate keepers" of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion.

Figure 1

Effects of the CCL5/CCR5 interactions in cancer. Cancer cells secrete CCL5 or induce fibroblasts to secrete CCL5 which act in a paracrine or autocrine fashion on CCR5-positive tumor cells to sustain their proliferation, to recruit immunosuppressive cells (T-reg cells, monocyte), to induce osteoclasts activation and bone metastasis, to induce neoangiogenesis, and to guide tumor cells to disseminate to distant organs.

Figure 2

Interactions among cHL cells and the microenvironment. Proposed role of the CCL5/CCR5 axis in Hodgkin Lymphoma leading to tumor cell proliferation and microenvironment formation. CCL5 produced by cHL cells may represent an autocrine growth factor. CCL5 secreted by T cells or fibroblasts may represent a paracrine growth factor. CD40L increases CCL5 secretion by cHL cells and they induce fibroblasts to secrete CCL5. CCL5 secreted by cHL (direct recruitment) or fibroblasts activated by HL cells (indirect recruitment) may in turn recruit CD4+ T cells, T-reg cells, eosinophils, and mast cells.

Figure 3

CCL5 and CCR5 as therapeutic targets in cancer. Different strategies proposed to disrupt the CCL5/CCR5 axis. (a) CCL5/CCL5 interaction may be inhibited by CCR5 antagonists. (b) CCL5 secretion by tumor cells or by MSCs of the tumor microenvironment may be decreased by treatment with chemotherapeutic agents. (c) The interactions between tumor cells and MSCs, mediated by EGF/EGFR pair, leading to increased CCL5 secretion by MSCs, may be inhibited by the EGFR-tyrosine kinase inhibitor gefitinib.