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• W2480451596 abstract "Tumor stromal cell components, in particular cancer associated fibroblasts, play an important role in cancer progression. Few studies have focused on stromal fibroblast targeting by oncolytic viruses. The urokinase receptor (uPAR) is a clinically and biologically validated target, which is overexpressed in tumor and stromal cells compared to non-cancer tissues. MV-h-uPA and MV-m-uPA are fully retargeted oncolytic measles viruses directed against human and murine uPAR, respectively, which have shown in vitro and in vivo safety and antitumor effects. Species specific retargeted viral vectors allow to dissect the specific effects of the viruses on murine vs. human tissues in xenograft models. Our aim is to characterize the in vitro and in vivo effects of stromal targeting by oncolytic measles virus via uPAR, with a focus on tumor fibroblasts. In vitro, MV-h-uPA and MV-m-uPA preferentially infected and induced cytotoxicity in human cancer associated fibroblasts (CAF 19, CAF 23) as well as murine fibroblasts (3T3), compared to non-tumorigenic fibroblasts. Murine-murine and human-human fibroblast to cancer cell viral transfer via heterofusion was observed after fibroblast infection by species specific MV-uPA, in breast, colon and renal cancer models, while no viral transfer was observed between cells of different species. In vivo, systemic administration of the murine uPA retargeted virus (MV-m-uPA) significantly decreased tumor progression and prolonged survival in a human breast cancer xenograft model (MDA-MD231), where the host stroma expresses murine uPAR (target of MV-m-uPA). Tumor studies revealed induction of apoptosis (TUNEL assay), while no significant effects on cancer cell proliferation was observed. Dual staining for measles virus nucleocapsid proteins and fibroblasts markers demonstrated viral infection of fibroblasts in treated tumors. Gene expression studies using murine as well as human specific arrays were performed to characterize the effects of stromal targeting by the murine retargeted virus on murine stroma as well as the indirect effects on human cancer cells in vivo. In conclusion, for the first time our results show feasibility and antitumor effects of stromal fibroblast targeting by oncolytic measles virus via uPAR and demonstrate that stromal fibroblasts are viable targets for oncolytic virotherapy. Studies characterizing other stromal cell components and evaluation of the molecular changes in the tumor stroma as result of viral infection are underway. Citation Format: Yuqi Jing, Julia Zaias, Jaime Merchan. Tumor fibroblast targeting via uPAR retargeted measles virus: In vitro and in vivo effects. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3745." @default.
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• W2480451596 date "2016-07-15" @default.
• W2480451596 modified "2023-09-25" @default.
• W2480451596 title "Abstract 3745: Tumor fibroblast targeting via uPAR retargeted measles virus:In vitroandin vivoeffects" @default.
• W2480451596 doi "https://doi.org/10.1158/1538-7445.am2016-3745" @default.
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