For example, at relatively early stages of the malignancy process, chemokines can induce the infiltration of lymphocytes that have the potential to raise anti-tumor activities. In line with their key roles in regulating leukocyte trafficking under physiological conditions, chemokines and their G protein-coupled receptors (GPCRs) are central players in dictating the types and amounts of leukocytes that are recruited to tumors and metastases ( 4– 7). In addition, chemotactic cues that are largely mediated by chemokines and their receptors are strongly involved in the dynamic processes of tumor development and progression. These processes are controlled by a very large array of chemotactic molecules-chemokines and others-that act in an orchestrated manner to achieve accuracy, fine-tuning, and precise turn-on/turn-off signals in regulating leukocyte influxes ( 1– 3).
Leukocyte trafficking is the hallmark of immune integrity, directing the appropriate positioning of lymphocytes and myeloid cells in tissues during acquired immunity, inflammation, and immune homeostasis. The mechanisms involved in chemokine activities and the signals delivered by their receptors are described, and the clinical implications of these findings are discussed. CXCR7, a member of the subgroup of atypical chemokine receptors (ACKRs) known also as ACKR3, opens the gate for discussion of atypical activities of additional ACKRs in cancer: ACKR1 (DARC, Duffy), ACKR2 (D6), and ACKR4 (CCRL1). In addition, non-conventional activities of CXCL12 which is a key regulator of tumor progression, and its CXCR4 receptor are described, alongside with the other CXCL12-binding receptor CXCR7 (RDC1). To illustrate this expanding array of atypical chemokine activities at the cancer setting, the review focuses on major metastasis-promoting inflammatory chemokines-including CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES)-and their receptors.
The review also describes atypical effects of chemokines at the tumor microenvironment: their ability to up-regulate/stabilize the expression of inhibitory immune checkpoints and to reduce the efficacy of their blockade to induce bone remodeling and elevate osteoclastogenesis/bone resorption and to mediate tumor-stromal interactions that promote cancer progression. Within this scope, this review article addresses the roles of chemokines and their receptors at atypical levels that are exerted on the cancer cell themselves: promoting tumor cell proliferation and survival controlling tumor cell senescence enriching tumors with cancer stem cells inducing metastasis-related functions such as epithelial-to-mesenchymal transition (EMT) and elevated expression of matrix metalloproteinases (MMPs) and promoting resistance to chemotherapy and to endocrine therapy. However, the array of chemokine activities in cancer expands beyond such “typical” migration-related processes and includes chemokine-induced/mediated atypical functions that do not activate directly motility processes these non-conventional chemokine functions provide the tumor cells with new sets of detrimental tools. In parallel, chemokines elevate additional pro-cancerous processes that depend on cell motility: endothelial cell migration (angiogenesis), recruitment of mesenchymal stem cells (MSCs) and site-specific metastasis. Being key leukocyte attractants, chemokines promote the presence of inflammatory pro-tumor myeloid cells and immune-suppressive cells in tumors and metastases. The anti-tumor activities of some members of the chemokine family are often overcome by the functions of many chemokines that are strongly and causatively linked with increased tumor progression.