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.

Keywords: atypical chemokine activities in cancer; atypical chemokine receptors; breast cancer; chemokines; classical chemokine receptors.

Figure 1

Typical and atypical pro-tumor activities of chemokines and their receptors in cancer. The chemokine family contains many different members, some of which can limit tumor progression for example by inducing the recruitment of cytotoxic immune cells to tumors, or by inducing angiostasis (e.g., CXCR3). However, extensive investigations of chemokine roles in cancer indicate that chemokine activities that promote tumor development and progression are very common and often dominate the malignancy process. Being prime regulators of leukocyte migration in the immune context, chemokines are primarily considered as inducers of cellular motility. Accordingly, chemokine activities that promote tumor progression via induction of directional cell motility—of leukocytes, endothelial cells, stromal cells and cancer cells—are regarded in the scope of this review as “Typical”. Very much like the “Typical” chemokine activities, also those that do not directly affect cellular motility and are thus termed herein “Atypical”, can be exerted on the tumor cells or on the TME (tumor microenvironment). By addressing most of these aspects in breast cancer, we emphasize in this review article the atypical activities of chemokines in cancer (thus given a higher proportion in this drawing, but not necessarily so in the actual cancer setting). In the “Typical” part, we mention that typical chemokine-induced migration can lead to homing of cancer cells at specific metastatic sites and to remodeling of the tumor landscape by recruiting leukocytes, inducing angiogenesis through endothelial cell migration, and attracting MSCs that can then differentiate to CAFs. In parallel, in the “Atypical” part, we describe the roles of chemokines in reinforcing (1) the aggressiveness of the tumor cells, by elevating tumor cell proliferation and survival, regulating senescence, enriching tumors for CSCs, inducing EMT and MMP production and elevating resistance to chemotherapy and endocrine treatments; and (2) the pro-metastatic nature of the TME, by interfering with the activities of ICBs, remodeling the bone niche by elevating osteoclastogenesis and bone resorption, and promoting tumor-stroma interactions that contribute to elevated malignancy. Together, all of these chemokine effects—typical and atypical—eventually lead to elevated metastasis and worsening of disease course. *Anti-metastatic activities in cancer: Under specific settings, the pro-metastatic activities of chemokines can be inhibited by other chemokines that act through classical chemokine receptors (e.g., CXCR3) or by atypical chemokine receptors (ACKRs). Such tumor-inhibitory activities of ACKRs have been well-documented for ACKR1 and ACKR4, whereas ACKR2 was mostly reported as an anti-malignancy element, with pro-tumor activities reported as well. In contrast, CXCR7/ACKR3 is mainly characterized as tumor-enhancing factor, although its roles in malignancy are complex, can be anti-tumorigenic and often reflect its interactions with CXCR4, the other receptor that binds CXCL12.