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.
Highlights
Tumors undergo an angiogenic switch when the balance between pro-angiogenic and anti-angiogenic factors is perturbed, leading to tumor outgrowth and expansion [1,2,3]
Our previous studies demonstrated that the induction of bone marrow derived pro-angiogenic cells (BMDCs)-mediated angiogenesis, CEPs, can contribute to tumor re-growth, and it is partially mediated by SDF-1 and G-CSF [11,16,32]
We focused on the contribution of tumor cells to angiogenesis
Summary
Tumors undergo an angiogenic switch when the balance between pro-angiogenic and anti-angiogenic factors is perturbed, leading to tumor outgrowth and expansion [1,2,3]. Other bone marrow derived cell (BMDC) types, such as myeloid derived suppressor cells (MDSCs), hemangiocytes, and Tie-2 expressing monocytes (TEMs) were found to contribute to systemic tumor angiogenesis by supporting blood vessel growth and function via different paracrine mechanisms [6]. We recently demonstrated that the level of EPCs in the peripheral blood of mice rises rapidly in response to various cytotoxic agents, including chemotherapy and vascular disrupting agents (VDAs). These cells home to the treated tumor site, induce angiogenesis and aid in tumor cell repopulation leading to tumor re-growth [10,11]. Studies have demonstrated that it is the response of the host, rather than the tumor cells themselves, to such anticancer therapies, that facilitates systemic angiogenesis [15,16]
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