TY  - JOUR
AU  - Morein, Dina
AU  - Erlichman, Nofar
AU  - Ben-Baruch, Adit
TI  - Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy.
JO  - Frontiers in immunology
VL  - 11
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2025-02461
SP  - 952
PY  - 2020
N1  - #DKFZ-MOST-Ca187#
AB  - 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.
KW  - Animals
KW  - Antineoplastic Agents: therapeutic use
KW  - Cell Movement: drug effects
KW  - Chemokines: metabolism
KW  - Drug Resistance, Neoplasm
KW  - Epithelial-Mesenchymal Transition
KW  - Humans
KW  - Neoplasms: drug therapy
KW  - Neoplasms: immunology
KW  - Neoplasms: metabolism
KW  - Neoplasms: pathology
KW  - Neoplastic Stem Cells: immunology
KW  - Neoplastic Stem Cells: metabolism
KW  - Neoplastic Stem Cells: pathology
KW  - Receptors, Chemokine: metabolism
KW  - Signal Transduction
KW  - Tumor Microenvironment
KW  - atypical chemokine activities in cancer (Other)
KW  - atypical chemokine receptors (Other)
KW  - breast cancer (Other)
KW  - chemokines (Other)
KW  - classical chemokine receptors (Other)
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - Chemokines (NLM Chemicals)
KW  - Receptors, Chemokine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:32582148
C2  - pmc:PMC7287041
DO  - DOI:10.3389/fimmu.2020.00952
UR  - https://inrepo02.dkfz.de/record/306232
ER  -