Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors |
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Authors: | Paulina H Liang Fang Tian Yi Lu Biyan Duan Donna B Stolz Lu-Yuan Li |
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Institution: | (1) Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;(2) University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;(3) College of Pharmacy, Nankai University, Tianjin, China; |
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Abstract: | Bone marrow (BM)-derived endothelial progenitor cells (EPC) have a critical role in tumor neovascularization. Vascular endothelial
growth inhibitor (VEGI) is a member of the TNF superfamily (TNFSF15). We have shown that recombinant VEGI suppresses tumor
angiogenesis by specifically eliminating proliferating endothelial cells (EC). We report here that treatment of tumor bearing
mice with recombinant VEGI leads to a significantly decreased population of BM-derived EPC in the tumors. We transplanted
whole bone marrow from green fluorescent protein (GFP) transgenic mice into C57BL/6 recipient mice, which were then inoculated
with Lewis lung carcinoma (LLC) cells. Intraperitoneal injection of recombinant VEGI led to significant inhibition of tumor
growth and decrease of vasculature density compared to vehicle-treated mice. Tumor implantation yielded a decrease of BM-derived
EPC in the peripheral blood, while VEGI-treatment resulted in an initial delay of such decrease. Analysis of the whole bone
marrow showed a decrease of Lin−-c-Kit+-Sca-1+ hematopoietic stem cell (HSC) population in tumor bearing mice; however, VEGI-treatment caused a significant increase of
this cell population. In addition, the number of BM-derived EPC in VEGI-treated tumors was notably less than that in the vehicle-treated
group, and most of the apoptotic cells in the VEGI-treated tumors were of bone marrow origin. These findings indicate that
VEGI inhibits BM-derived EPC mobilization and prevents their incorporation into LLC tumors by inducing apoptosis specifically
of BM-derived cells, resulting in the inhibition of EPC-supported tumor vasculogenesis and tumor growth. |
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