Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61.
Oncolytic viral therapy is under evaluation for toxicity and efficacy in clinical trials relating to several different tumors. We report a significant increase in the angiogenic index of oncolytic virus (OV)-treated glioma-matrigel implants (2.83-fold, P < 0.02). In a rat intracranial glioma model, large tumors from OV-treated animals were significantly more angiogenic than the phosphate-buffered saline (PBS)-treated control tumors (OV: 101 +/- 21.6; PBS: 19.8 +/- 10; P = 0.0037). Transcript profiling of OV-treated tumors revealed dysregulation of several transcripts involved in glioma angiogenesis. OV-mediated induction of CYR61 gene expression (8.94-fold, P = 0.001) correlated significantly with the presence of OV in tumor tissue in vivo (R = 0.7, P < 0.001). Further, induction of CYR61 mRNA and protein were confirmed in multiple human cancer cell lines and primary human tumor-derived cells in vitro, and in tumor lysate and cerebrospinal fluid (CSF) in vivo. Finally, we show that treatment of glioma cells with Cilengitide, known to counter CYR61-induced integrin activation, significantly suppressed the proangiogenic effect of OV treatment of gliomas (P < 0.05).
Kurozumi
Kazuhiko
K
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio, USA.
Hardcastle
Jayson
J
Thakur
Roopa
R
Shroll
Joshua
J
Nowicki
Michal
M
Otsuki
Akihiro
A
Chiocca
E Antonio
EA
Kaur
Balveen
B
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000235:genetics* / Q000378:metabolism; D005910:Glioma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C501848:CCN1 protein, human; C501849:CCN1 protein, rat; D055515:Cysteine-Rich Protein 61; D012333:RNA, Messenger