Does the vesicular stomatitis virus really have a selective oncolytic effect in human cancer?

Several studies reported that oncolytic viruses are a promising novel therapeutic approach for human aggressive cancer.1-4 Vesicular stomatitis virus (VSV), an RNA virus belonging to the Rhabdoviridae family, possesses intrinsic oncolytic properties that permit cancer cell destruction while sparing normal cells.5, 6 The oncolytic capacity of VSV has been established in vitro and in vivo; VSV infection selectively kills a large panel of human tumor cell lines.6 However, the outcome of VSV in human normal and cancerous cells from same patients has not been investigated yet. We recently examined the effect of VSV on several human primary normal and cancer cells, from the same patients, including prostate, cervical, breast, and oral, which we have established in our laboratory. We found that VSV replicates and consequently kills normal and cancer cells within 24 to 48 hours in the majority of cases. Moreover, we noted that VSV kills normal breast and ovarian epithelial cells as well as their matched immortalized cells by E6/E7 genes of human papillomavirus (HPV) type 16 (unpublished data). Alternatively, we observed that VSV are not able to kill human normal mammary and ovarian epithelial cells carrying 3450delCAAG-BRCA1 and 3773delTT-BRCA2 mutations, respectively, which are immortalized by E6/E7 of HPV type 16 (Fig. 1). More contritely, restoration of BRCA1 and BRCA2 expression in these cell lines did not affect the ability of VSV to replicate in these cells; whereas the stable transfection of full length BRCA1 and BRCA2 cDNA restores cell cycle progression and blocks cell motility and invasion induced by these specific mutations in human primary breast and ovarian cells7; and unpublished data in contrast, the control cells of human normal mammary epithelial cells expressing E6/E7 onco-proteins of HPV type 16 were killed by the VSV. In conclusion, our study shows clearly that VSV instillation therapy is questioned since the selective ability of this virus to kill cancer cells while sparing the normal cells is not confirmed, based on our study of matched normal and cancer cell lines established from the same patients; which suggests that VSV could replicate in normal as well as cancer cells in the majority of the cases. Therefore, we believe that VSV cannot be used as a new therapeutic approach targeting human cancers; however, thorough studies of VSV replication and its interaction with other genes are necessary in order to be able to determine its real role as a promising approach to cancer therapy. Effect of VSV in human normal mammary and ovarian cells as well as BRCA1 and BRCA2 mutated cells, respectively, immortalized by E6/E7 of HPV type 16. We note that VSV replicates and induces cell apoptosis in normal mammary and ovarian cells but not in BRCA1 and BRCA2 mutated cell lines. The authors are thankful to Mrs. A. Kassab for her critical reading of the manuscript. Amber Yasmeen, Zhang Li, Ala-Eddin Al Moustafa.