A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

TLDR

SDF‑1 regulates diverse biological processes, and these effects are traditionally attributed to the single receptor CXCR4. This study aims to characterize CXCR7, an alternate receptor that binds SDF‑1 and the chemokine I‑TAC with high affinity. CXCR7 binds SDF‑1 and I‑TAC with high affinity, yet its activation does not trigger Ca²⁺ mobilization or cell migration. CXCR7 is expressed on many tumor and endothelial cells, promotes cell growth, survival, and adhesion, and its inhibition suppresses tumor growth in vivo, supporting its therapeutic potential.

Abstract

The chemokine stromal cell–derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell α chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.