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Modulation of bone marrow-derived endothelial progenitor cells by vascular endothelial growth inhibitor (VEGI)

Liang, Paulina Huang (2011) Modulation of bone marrow-derived endothelial progenitor cells by vascular endothelial growth inhibitor (VEGI). Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Bone marrow (BM)-derived endothelial progenitor cells (EPCs) have a critical role in tumor vasculogenesis, mobilizing to tumors and supporting de novo formation of blood vessels essential for tumor growth and metastasis. Vascular endothelial growth inhibitor (VEGI; TL1A) is a member of the tumor necrosis superfamily (TNFSF15) and is produced predominantly by endothelial cells (ECs). VEGI has been shown to act in an autocrine manner by specifically targeting ECs to inhibit their proliferation and induce apoptosis, resulting in elimination of ECs in established tumor vasculature and inhibition of angiogenesis. However, it remains unclear whether VEGI exerts its function solely on fully differentiated ECs or if it is able to modulate BM-derived EPCs as well. Here, the effect of recombinant VEGI on BM-derived EPC function is evaluated in an effort to establish the potential therapeutic value of VEGI. We found that VEGI inhibits the differentiation of EPCs from murine BM under EC stimulating culture conditions. Consistently, VEGI treatment decreases the capability of the cells to adhere, migrate and form capillary-like structures necessary for vascular formation. Additionally, differentiated BM-derived EPCs in cultures underwent apoptosis in response to VEGI treatment. To investigate the impact of VEGI on BM-derived EPC-supported tumor vasculogenesis, mice bearing Lewis lung carcinoma (LLC) tumors were treated with intraperitoneal injection of recombinant VEGI. VEGI treatment significantly decreased the population of BM-derived EPCs found in the tumors while increasing their population in the bone marrow. Furthermore, an overall increase in apoptosis of BM-derived cells at the tumor site was observed after VEGI treatment. Our results indicate VEGI prevents incorporation of BM-derived EPCs into LLC tumors, resulting in the inhibition of EPC-supported tumor vasculogenesis and tumor growth. Together, these findings suggest that VEGI takes part in the modulation of tumor vasculogenesis by inhibiting BM-derived EPC differentiation and mobilization as well as inducing apoptosis. These studies yield important insights into the function of VEGI in postnatal vasculogenesis, helping to facilitate the development of therapeutic uses of VEGI in cancer.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Liang, Paulina Huangpahst33@pitt.eduPAHST33
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStolz, Donna Bdstolz@pitt.eduDSTOLZ
Committee MemberPflug, Beth
Committee MemberLi,
Committee MemberCheng,
Committee MemberCheng,
Date: 13 April 2011
Date Type: Completion
Defense Date: 2 December 2010
Approval Date: 13 April 2011
Submission Date: 12 April 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: EPC; neovascularization; VEGI
Other ID:, etd-04122011-233013
Date Deposited: 10 Nov 2011 19:36
Last Modified: 15 Nov 2016 13:39


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