The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Abstract

Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4 + BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4 + VEGFR1 + hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.

Forkhead transcription factors regulate expression of the chemokine receptor CXCR4 in endothelial cells and CXCL12-induced cell migration

“…The CXCR4-CXCL12 signaling pathway has been shown to induce neovascularization under pathological conditions such as tumor growth and myocardial infarction by promoting the growth of pre-existing blood vessels and/or recruitment of CXCR4+ endothelial progenitor cells (EPCs) from the bone marrow [28,29]. Accordingly, we have found that human FOXC1 and FOXC2 are expressed in tumor blood vessels as well as EPCs (unpublished results).…”

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells

“…CXCR4 inhibition prevented accelerated tumor growth after chemotherapy by blocking the recruitment of mobilized endothelial progenitor cells and abrogated tumor regrowth after radiotherapy by preventing the influx of vasculgenic CD11b + BMD cells into irradiated tumors (Kioi et al, 2010). Thus, the SDF-1/CXCR4 axis in considered an important hub in the regulation of neo-vascularization during tumor growth (Petit et al, 2007). Since a CXCR4 antagonist (plerixafor) is now clinically available, one may consider the design of studies in patients with solid cancer testing the potential benefits of CXCR4 inhibition.…”

Endothelial progenitor cells for cancer gene therapy

“…18,30,33 Recent data show that stromal-derived factor 1 (SDF-1/CXCL12) contributes to the recruitment of EPCs to tumors and their retention in the tumor vessels. 27,34,35 …”