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Vstat120 modulates inhibits oncolytic viral therapy induced angiogenesis and innate pro-inflamatory response, augmenting oncolytic viral thereapy of glioblastom multiforme

Hardcastle, Jayson James
http://rave.ohiolink.edu/etdc/view?acc_num=osu1305920551

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Glioblastoma multiform is one of the deadliest cancers known and represents approximately 40% of all primary brain tumors diagnosed. A major histopathological hallmark of these tumors is increased vascularity and micro-vascular proliferation. Work recently completed by our lab showed increased micro-vascular density (MVD) following oncolytic virus (OV) therapy. To this end we created a novel armed OV termed RAMBO (Rapid Anti-angiogenesis Mediated By Oncolytic virus) that contains the transgene econding Vasculostatin (Vstat120). Vstat120 is the extracellular fragment of BAI1 that is proteolytically processed at a conserved G protein coupled receptor proteolytic cleavage site (GPS), resulting in the release of secreted Vstat120. Our work with RAMBO, in two GBM mouse xenografts studies, showed a significant enhancement of survival compared to the control virus, HSVQ. Additionally, subcutaneous GBM xenografts treated with RAMBO had a significant reduction in tumor MVD and vessel perfusion. In 2007 Park et. Identified BAI-1 as a phagocytic receptor expressed on cells of a monocytic lineage. Additionally, a synthetic peptide with 5 Thrombospondin Type-1 repeats and an integrin RGD binding domain was able to inhibit BAI-1 phagocytosis of apoptotic bodies. Our results with RAMBO showed that conditioned medium (CM), derived from infected glioma cells, significantly inhibits N13 and BV2 murine microglia phagocytosis of carboxylate coated beads and microglia migration. In vivo FACS analysis of microglia and monocytes isolated from mice bearing U87Delta-EGFR intracranial gliomas treated with RAMBO, HSVQ or PBS revealed a significant increase in monocyte infiltration into tumors treated by HSVQ; while no change in microglia or monocyte infiltration was found for mice treated with RAMBO compared to PBS treated tumors. FACS analysis for monocyte activation markers Ly6-C, MHC-II, CD86, and CD206 revealed a significant increase in receptor expression levels for monocytes issoalted from HSVQ treated mice compared to RAMBO and PBS treated mice. No significant difference was found for the receptor expression levels found for RAMBO treated mice compared to PBS treated mice. QPCR experiments using murine microglia specific primers for co-culture experiments with human glioma cells infected with RAMBO or HSVQ showed a significant down regulation of mRNA for all Type-1 and Type-2 IFNs and all inflammatory cytokines and chemokines tested for microglia co-cultured with RAMBO infected glioma cells compared to HSVQ. OV gene copy assays from microglia co-cultured with RAMBO or HSVQ treated glioma cells showed a significant increase in RAMBO gene copy vs. HSVQ gene copy 12 hrs post co-culture initiation. In-vivo QPCR for ICP4 mRNA and OV gene copy from intracranial U87Delta-EGFR and Gli26DeltaEGFR-H2B-RFP subcutaneous tumors, respectively, treated with either RAMBO or HSVQ showed a dramatic increase in ICP4 mRNA and OV gene copy for RAMBO treated tumors compared to HSVQ treated tumors. Our results indicate that Vstat120 is also able to modulate the monocytic/microglia innate pro-inflammatory response to OV therapy, resulting in increased OV replication in vivo and in vitro.
Blaveen Kaur, PhD (Advisor)
E.A. Chiocca, MD, PhD (Committee Co-Chair)
William Carson, MD (Committee Member)
James Waldman, PhD (Committee Member)
177 p.
Biomedical Research; Immunology; Neurology; Oncology; Virology
Oncolytic Virus; Glioma; Angiogenesis; Tumor Micro-environment; Vstat120; Microglia; Macrophages; Innate Immune Response; Inflammation; Anti-angiogenic; RAMBO

Recommended Citations

Citations

  • Hardcastle, J. J. (2011). Vstat120 modulates inhibits oncolytic viral therapy induced angiogenesis and innate pro-inflamatory response, augmenting oncolytic viral thereapy of glioblastom multiforme [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305920551

    APA Style (7th edition)

  • Hardcastle, Jayson. Vstat120 modulates inhibits oncolytic viral therapy induced angiogenesis and innate pro-inflamatory response, augmenting oncolytic viral thereapy of glioblastom multiforme. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1305920551.

    MLA Style (8th edition)

  • Hardcastle, Jayson. "Vstat120 modulates inhibits oncolytic viral therapy induced angiogenesis and innate pro-inflamatory response, augmenting oncolytic viral thereapy of glioblastom multiforme." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305920551

    Chicago Manual of Style (17th edition)

osu1305920551
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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.