Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis

Abstract

Angiogenesis and the development of a vascular network is required for tumor progression, and involves release of angiogenic factors, including vascular endothelial growth factor (VEGF), from both malignant and stromal cell types1. Infiltration by cells of the myeloid lineage is a hallmark of many tumors, and in many cases the macrophages in these infiltrates express VEGF2. Here we show that deletion of inflammatory cell-derived VEGF attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumors. Vasculature in tumors lacking myeloid cell-derived VEGF was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF decreases VEGFR2 phosphorylation in tumors, even though overall VEGF levels in the tumors are unaffected. However, myeloid deletion of VEGF resulted in an accelerated tumor progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumor cell death and decreased tumor hypoxia. Furthermore, loss of myeloid cell VEGF increased tumor susceptibility to chemotherapeutic cytotoxicity. This demonstrates that myeloid-derived VEGF is essential for tumorigenic alteration of vasculature and signaling to VEGFR2, and that these changes act to retard, not promote, tumor progression.

Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development

“…TAM-derived VEGF acts signifi cantly on angiogenesis and tumor development, whereas down-regulating VEGF levels induces antitumorigenesis (Bolat et al, 2006). The deletion of the VEGF gene in macrophages decreases tumor angiogenesis (Stockmann et al, 2008). Anti-bodies against VEGF exert a large inhibitory effect on tumor growth (Kim et al, 1993).…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…These studies suggest that TAMs control drug delivery through regulating vessel functionality and leakiness. In support of this notion, deletion of pro-angiogenic molecules, such as VEGFA and PlGF, in myeloid cells and bone marrow-derived cells, respectively, decreases vascular leakiness [36,41] and increases the potency of cyclophosphamide on transplanted tumors [41].…”

Anticancer Effect of COX-2 Inhibitor DuP-697 Alone and in Combination with Tyrosine Kinase Inhibitor (E7080) on Colon Cancer Cell Lines

“…VEGF is involved in tumor angiogenesis by inducing endothelial cell proliferation, migration and survival (Darakhshan et al, 2013). Its importance in CRC 3114 growth and development has been documented (Stocmann et al, 2008).…”