Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy

Abstract

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. Being key leukocyte attractants, chemokines promote the presence of inflammatory pro-tumor myeloid cells and immune-suppressive cells in tumors and metastases. 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. 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. 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. 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. 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. 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). 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). The mechanisms involved in chemokine activities and the signals delivered by their receptors are described, and the clinical implications of these findings are discussed.

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

“…Chemokines and their receptors not only drive the trafficking of leukocytes inside the tumor mass but also contribute to most aspects of tumor cell biology ( 1 ). High expression of CXCR4 is observed in hematological malignancies ( 57 – 59 ) and in many types of solid tumors, including melanomas and kidney, lung, brain, prostate, breast, pancreas and ovarian tumors ( 2 , 3 ), where it correlates with poor prognosis ( 59 ).…”

“…They are also involved in tumor metastasis and invasion, and in the extension of neurites and axons of neurons (a part of a cell moves, while the cell body stays put). How chemokines and their receptors recruit hematopoietic cells to injured sites and tumors has been intensely investigated, whereas their involvement in the control of cell proliferation is less explored ( 1 ). Among chemokine receptors, CXCR4 is the most widely expressed, and is involved in numerous physiological and pathological conditions.…”

Impact of inflammation and immunotherapy in renal cell carcinoma (Review)

“…The activity of CXCR4 is mainly γ-mediated; however, CXCR7 is considered to be an atypical G protein-coupled receptor, as it does not cause intracellular Ca 2+ release when bound to a ligand ( 107 ). Some studies have shown that CXCR7 is a DcR that isolates extracellular CXCL12 or regulates the CXCR4 signaling pathway by forming a CXCR7-CXCR4 heterodimer ( 108 , 109 ). High expression of CXCR7 in human cancer types such as bladder cancer, glioma, colorectal cancer, ovarian cancer and breast cancer, and in tumor-associated blood vessels, may be critical for tumor cell survival, adhesion and growth ( 110 – 115 ).…”

Functions of the CXCL12 Receptor ACKR3/CXCR7—What Has Been Perceived and What Has Been Overlooked

“…Although potential mechanisms capable of sculpting the cellular CXCL12 system such as ligand and receptor dimerization /oligomerization, receptor heteromerization, RGSs, and Grks emerged over recent years, the direct proof if and how these mechanisms dictate the molecular organization of the CXCL12 system in distinct cells still awaits experimental clarification. With the emerging role of ACKR3 and CXCR4 as therapeutic targets central to cancer, cardiovascular diseases, and inflammatory processes (Morein et al, 2020;Mousavi 2020;Wang et al, 2018b) knowledge of these sculpting mechanisms is becoming more and more eminent as they will allow for optimized therapeutic strategies. Finally, we hope that our present review will spark new interest into the function of ACKR3 which, as we feel, partially evaporated with its classification as an atypical chemokine receptor.…”