Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas

Abstract

Local recurrence of glioblastomas is a major cause of patient mortality after definitive treatment. This review discusses the roles of the chemokine stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4 (CXCR4) in affecting the sensitivity of glioblastomas to irradiation. Blocking these molecules prevents or delays tumour recurrence after irradiation by inhibiting the recruitment of CD11b+ monocytes/macrophages that participate in revascularising the tumour. We review the literature pertaining to the mechanism by which revascularisation occurs following tumour irradiation using experimental models. Areas of interest and debate in the literature include the process by which endothelial cells die after irradiation and the identity/origin of the cells that reconstitute the tumour blood vessels after injury. Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation.

Figure 1

Model of the main contributions of bone marrow-derived cells (BMDCs) and cytokines that promote restoration of tumour vasculature following irradiation. Prior to irradiation, tumour growth is governed largely by local angiogenesis. When local angiogenesis is inhibited by irradiation, growth of the tumour vasculature (essential for recurrence of the tumour) can only occur from circulating cells, of which BMDCs are an essential component. Following irradiation, the tumour becomes more hypoxic and HIF-1 is increased as the tumour attempts to regrow. This induces SDF-1 and promotes the recruitment of CD11b+ monocytes/macrophages and retention of these cells in the tumour. Stromal cell-derived factor-1/CXC chemokine receptor 4 is the key interaction for the influx of BMDCs as AMD3100, an inhibitor of CXCR4/SDF-1, and antibodies against CXCR4 block the recruitment and/or tumour retention of the BMDCs, inhibit restoration of the tumour vasculature, and prevent tumour recurrence. The various inhibitors and the points in the cycle at which they act are shown in boxes. Reproduced from Kioi et al (2010) with permission. (A) Pre-irradiation; (B) post-irradiation.