Bone marrow-derived endothelial progenitor cells (EPC) have been shown to be a critical component of supporting tumor neovascularization. We have shown in a variety of cancer and angiogenesis models that recombinant vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits angiogenesis and tumor growth via specific elimination of mature endothelial cells (EC) in established tumor vasculature. We report here that VEGI treatment leads to a significantly decreased population of EPC in tumors. We transplanted whole bone marrow from green fluorescent protein (GFP) transgenic mice into C57BL/6 recipient mice. The mice were then inoculated with Lewis Lung cancer (LLC) cells and treated with VEGI or vehicle. In the tumors of the VEGI-treated group, we saw both a significant inhibition of tumor growth and decreased density of CD31+ vasculature compared to vehicle treated mice. Flow cytometric analysis of the peripheral blood of tumor bearing mice revealed an initial increase of EPCs derived from the bone marrow (GFP+Flk1+) prior to the timeframe when EPCs are incorporated into the tumor. After this timeframe, the EPC in peripheral blood decreased markedly. Monitoring for EPC by GFP+CD31+ immunostaining, we found that the number of EPC in VEGI treated tumors notably decreased compared to that of the untreated group. EPC incorporation into the tumor vasculature of VEGI-treated mice was also less than that in the untreated group. TUNEL staining of the tumor sections showed a large extent of apoptosis overall in VEGI-treated tumors. These findings indicate that VEGI plays an important role in modulating bone marrow-derived EPC incorporation into LLC carcinomas, resulting in the inhibition of EPC supported tumor vasculogenesis and tumor growth.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1300.