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Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors

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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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Acknowledgments

This work is supported in part by grants to L.Y.L from The National Institute of Health (CA113875), Pennsylvania Department of Health, The Hillman Foundation, and The Ministry of Science and Technology of China (2009CB918901). We thank Dr. Hui Yu, Dr. Richard XuFeng, and Mr. Mark Ross for their skillful technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All experiments performed comply with the current laws of the United States of America.

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Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Paulina H. Liang, Fang Tian, Yi Lu, Donna B. Stolz & Lu-Yuan Li

  2. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Paulina H. Liang, Fang Tian, Yi Lu & Lu-Yuan Li

  3. College of Pharmacy, Nankai University, Tianjin, China

    Biyan Duan & Lu-Yuan Li

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  1. Paulina H. Liang
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  2. Fang Tian
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  3. Yi Lu
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  5. Donna B. Stolz
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Correspondence to Lu-Yuan Li.

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Liang, P.H., Tian, F., Lu, Y. et al. Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors. Angiogenesis 14, 61–68 (2011). https://doi.org/10.1007/s10456-010-9195-8

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  • DOI: https://doi.org/10.1007/s10456-010-9195-8

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