At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer

Abstract

Signaling through chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) regulates essential processes in normal physiology, including embryogenesis, tissue repair, angiogenesis, and trafficking of immune cells. Tumors co-opt many of these fundamental processes to directly stimulate proliferation, invasion, and metastasis of cancer cells. CXCR4 signaling contributes to critical functions of stromal cells in cancer, including angiogenesis and multiple cell types in the tumor immune environment. Studies in animal models of several different types of cancers consistently demonstrate essential functions of CXCR4 in tumor initiation, local invasion, and metastasis to lymph nodes and distant organs. Data from animal models support clinical observations showing that integrated effects of CXCR4 on cancer and stromal cells correlate with metastasis and overall poor prognosis in >20 different human malignancies. Small molecules, Abs, and peptidic agents have shown anticancer efficacy in animal models, sparking ongoing efforts at clinical translation for cancer therapy. Investigators also are developing companion CXCR4-targeted imaging agents with potential to stratify patients for CXCR4-targeted therapy and monitor treatment efficacy. Here, pre-clinical studies demonstrating functions of CXCR4 in cancer are reviewed.

Keywords: CXCL12; CXCR4 antagonist; CXCR4 inhibitor; chemokine; radioimaging; tumor.

FIGURE 1. CXCR4 signaling promotes tumor growth and organ-specific metastasis.

CXCR4 signaling promotes tumor growth in primary tumors from sites including prostate, breast, and brain. Various isoforms of CXCL12 produced by carcinoma-associated fibroblasts in a primary tumor environment activates CXCr4 signaling through G protein and β-arrestin-dependent pathways. CXCR4 activates Akt, ERK, mTOR, Rac, Rho, and other effector molecules to drive survival, proliferation, and actin assembly for migration and invasion. Truncating mutations in CXCR4 as present in WHIM syndrome increase signaling through the receptor and reduced circulating neutrophils and lymphocytes. CXCL12-CXCR4 signaling promotes metastasis to sites including lung, liver, brain, and bone. Inhibitors of CXCR4 reverse aggressive features of cancer cells, angiogenesis, and abnormalities in circulating leukocytes. Targeted imaging agents can detect expression of CXCR4, potentially informing selection of patients and measurements of treatment efficacy

FIGURE 2. CXCR4 in the tumor microenvironment.

CAF-produced CXCL12 acts on different TME cells and regulates the recruitment of immune cells. (1) CXCR4/CXCL12 axis stimulates endothelial cells promoting neovascularization, tumor growth and metastatic progression. (2) CXCL12/CXCR4 axis regulates trafficking and tissue localization of human HSC in the BM. (3) CXCR4/CXCL12 axis recruits BM derived myeloid cells promoting DC maturation and survival. (4–6) CXCL12 recruits immunosuppressive cells and excludes effector cells designing a “colder” TME that impair immunotherapy response. CXCL12 also redirects the polarization of effector Th1 cells into CD4⁺CD25⁻Foxp3⁻IL 10^high regulatory T cells