Oncolytic reovirus inhibits angiogenesis through induction of CXCL10/IP-10 and abrogation of HIF activity in soft tissue sarcomas
AuthorCarew, Jennifer S.
Espitia, Claudia M.
Mita, Monica M.
Mita, Alain C.
Nawrocki, Steffan T.
AffiliationUniv Arizona, Ctr Canc
MetadataShow full item record
PublisherIMPACT JOURNALS LLC
CitationOncolytic reovirus inhibits angiogenesis through induction of CXCL10/IP-10 and abrogation of HIF activity in soft tissue sarcomas 2017 Oncotarget
RightsCopyright: © Carew et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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AbstractThe tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been rigorously studied in soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-gamma-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells. Further analysis determined that Reolysin treatment possessed significant anti-angiogenic activity irrespective of RAS status. In addition to CXCL10 induction, Reolysin dramatically downregulated the expression of hypoxia inducible factor (HIF)-1 alpha, HIF-2 alpha and inhibited vascular endothelial growth factor (VEGF) secretion. CXCL10 antagonism significantly diminished the anti-angiogenic effects of Reolysin indicating that it is a key driver of this phenomenon. Xenograft studies demonstrated that Reolysin significantly improved the anticancer activity of the anti-angiogenic agents sunitinib, temsirolimus, and bevacizumab in a manner that was associated with increased CXCL10 levels. This effect was most pronounced following treatment with Reolysin in combination with temsirolimus. Further analysis in additional sarcoma xenograft models confirmed the significant increase in CXCL10 and increased anticancer activity of this combination. Our collective results demonstrate that Reolysin possesses CXCL10-driven anti-angiogenic activity in sarcoma models, which can be harnessed to enhance the anticancer activity of temsirolimus and other agents that target the tumor vasculature.
VersionFinal published version
SponsorsNIH/NCI [R01CA190789, R01CA172443]; Wipe Out Kids' Cancer Foundation; University of Arizona Cancer Center start-up funds; University of Arizona Cancer Center Support Grant from the NIH/NCI [P30CA023074]