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

Tseng D, Vasquez-Medrano DA, Brown JM - Br. J. Cancer (2011)

Bottom Line: 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.Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University, 269 Campus Drive West, CCSR Room 1255, Stanford, CA 94305, USA.

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.

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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.
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fig1: 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.

Mentions: We hypothesise that elevated levels of tumour SDF-1 caused by increased tumour hypoxia (resulting from gradual loss of ECs) following irradiation lead to accumulation of CXCR4-expressing monocytes/macrophages in the irradiated tumour. This is also suggested by data in the literature showing that the recruitment and retention of proangiogenic hematopoietic cells to sites of ischaemic tissue damage or to tumours is mediated by the interaction of the SDF-1 with CXCR4 (Ceradini et al, 2004; Aghi et al, 2006; Jin et al, 2006). Stromal cell-derived factor-1 functions as a hypoxia-inducible gene through the action of the transcription factor hypoxia inducible factor-1 (HIF-1). We have shown that irradiated tumours gradually lose vasculature after irradiation, thereby becoming increasingly hypoxic and upregulating HIF-1. Consistent with this, the HIF-1 inhibitor NSC 134754 prevents both the radiation-induced tumour accumulation of CD11b+ monocytes/macrophages and prevents tumour recurrence (Kioi et al, 2010). We and others have shown that SDF-1 levels are increased in irradiated tumours (Kioi et al, 2010; Kozin et al, 2010) and in the plasma following local tumour irradiation of intracranial GBM (unpublished data). A model showing the pathway by which CD11b+ monocytes/macrophages accumulate in irradiated tumours is shown in Figure 1. Also shown in Figure 1 are the points in the pathway that have been targeted therapeutically to prevent the regrowth of irradiated tumours in pre-clinical studies.


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

Tseng D, Vasquez-Medrano DA, Brown JM - Br. J. Cancer (2011)

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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111201&req=5

fig1: 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.
Mentions: We hypothesise that elevated levels of tumour SDF-1 caused by increased tumour hypoxia (resulting from gradual loss of ECs) following irradiation lead to accumulation of CXCR4-expressing monocytes/macrophages in the irradiated tumour. This is also suggested by data in the literature showing that the recruitment and retention of proangiogenic hematopoietic cells to sites of ischaemic tissue damage or to tumours is mediated by the interaction of the SDF-1 with CXCR4 (Ceradini et al, 2004; Aghi et al, 2006; Jin et al, 2006). Stromal cell-derived factor-1 functions as a hypoxia-inducible gene through the action of the transcription factor hypoxia inducible factor-1 (HIF-1). We have shown that irradiated tumours gradually lose vasculature after irradiation, thereby becoming increasingly hypoxic and upregulating HIF-1. Consistent with this, the HIF-1 inhibitor NSC 134754 prevents both the radiation-induced tumour accumulation of CD11b+ monocytes/macrophages and prevents tumour recurrence (Kioi et al, 2010). We and others have shown that SDF-1 levels are increased in irradiated tumours (Kioi et al, 2010; Kozin et al, 2010) and in the plasma following local tumour irradiation of intracranial GBM (unpublished data). A model showing the pathway by which CD11b+ monocytes/macrophages accumulate in irradiated tumours is shown in Figure 1. Also shown in Figure 1 are the points in the pathway that have been targeted therapeutically to prevent the regrowth of irradiated tumours in pre-clinical studies.

Bottom Line: 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.Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University, 269 Campus Drive West, CCSR Room 1255, Stanford, CA 94305, USA.

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.

Show MeSH
Related in: MedlinePlus