The versatile world of inflammatory chemokines in cancer

Abstract

Until recently, inflammatory chemokines were viewed mainly as indispensable gate keepers of immunity and inflammation. However, updated research indicates that members of this chemokine sub-family are important constituents of the tumor microenvironment, having multifaceted tumor-promoting roles in cancer. A very large number of studies indicate that many of the inflammatory chemokines are exploited by the tumor cells for their own benefit, and are actually skewed to the pro-malignancy phenotype. The different chemokines may be simultaneously expressed at the tumor site, having overlapping but also distinct tumor-promoting impacts. In general (except for the axis of CXCR3 and its ligands, that acts as a double-edged sword), the inflammatory chemokines induce immune imbalance at primary tumors and metastatic sites, doing so by promoting the presence and activation of tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and/or T regulatory cells (Treg). In parallel, immune suppression is ensued due to inhibition of Th1 cells and cytotoxic T lymphocytes (CTL). The chemokines also elevate metastasis-related processes, such as angiogenesis and osteoclastogenesis in the bone. Furthermore, they act directly on the tumor cells, promoting their proliferation, migration and invasion properties. Obviously, not all chemokines have the same pro-malignancy roles; however, chemokines that share the same receptor tend to have much in common in terms of their pro-cancerous activities. Accordingly, we will describe the roles of inflammatory chemokines in malignancy by using a receptor-based categorization: (1) CXCR1 and CXCR2 with their ELR+ CXC chemokine ligands, primarily CXCL8 (IL-8) but also CXCL1 (MGSA, GROα) and CXCL5 (ENA-78); (2) CXCR3 with its non-ELR CXC chemokine ligands: CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-Tac); (3) CCR2 and its ligands, mainly CCL2 (MCP-1); (4) CCR5 and its corresponding chemokines, with major emphasis on CCL5 (RANTES) and CCL3 (MIP-1α). Based on the findings obtained so far, we propose that inflammatory chemokines and their receptors are attractive therapeutic targets in malignancy, and discuss the expected difficulties in translating such approaches in the clinic.