Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Cancer Research (Impact Factor: 9.28). 10/2009; 69(19):7524-8. DOI: 10.1158/0008-5472.CAN-09-0381
Source: PubMed

ABSTRACT Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

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    ABSTRACT: Tumor derived microparticles (TMPs) have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs). Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.
    PLoS ONE 04/2014; 9(4):e95983. DOI:10.1371/journal.pone.0095983 · 3.53 Impact Factor
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    ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) modulate progression of certain solid tumors. The G-CSF- or GM-CSF-secreting cancers, albeit not very common are, however, among the most rapidly advancing ones due to a cytokine-mediated immune suppression and angiogenesis. Similarly, de novo angiogenesis and vasculogenesis may complicate adjuvant use of recombinant G-CSF or GM-CSF thus possibly contributing to a cancer relapse. Rapid diagnostic tools to differentiate G-CSF- or GM-CSF-secreting cancers are not well developed therefore hindering efforts to individualize treatments for these patients. Given an increasing utilization of adjuvant G-/GM-CSF in cancer therapy, we aimed to summarize recent studies exploring their roles in pathophysiology of solid tumors and to provide insights into some complexities of their therapeutic applications.
    Cancer Medicine 08/2014; 3(4). DOI:10.1002/cam4.239

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