An oncolytic adenovirus expressing soluble transforming growth factor-B type II receptor for targeting breast cancer: in vitro evaluation

In recent years, adenoviruses that selectively replicate in tumor cells have been developed. However, there is a tremendous need to improve their anticancer efficacy. We wish to investigate whether a strategy that combines the oncolytic effects of an adenoviral vector with simultaneous expression of soluble form of transforming growth factor-B type II receptor (sTGFBRII) offers a therapeutic advantage. We chose to target TGF-Bs because they play a pivotal role in late-stage tumorigenesis by enhancing tumor invasion and metastasis. A sTGFBRII cDNA was cloned in conditionally replicating adenoviral vector rAdsTRII and in a replication-deficient adenovirus Ad-sTRII. Infection of MDA-MB-231 breast cancer cells with rAdsTRII or Ad-sTRII followed by Western blot analysis indicated the expression of diffused glycosylated forms of sTGFBRII that were also secreted into the extracellular medium. The secreted proteins were shown to bind with TGF-B and antagonize TGF-B–induced p38 mitogenactivated protein kinase activity. However, marked differences in the replication potential of rAd-sTRII and Ad-sTRII were observed in breast tumor cells. Infection of MDAMB-231 cells with rAd-sTRII resulted in cytotoxicity and significant increase in the adenoviral titers that were comparable with a wild-type adenovirus dl309. However, Ad-sTRII was much less toxic to the tumor cells, and the viral titers of Ad-sTRII remained relatively unchanged. These results suggest that the infection of breast tumor cells with conditionally replicating adenoviral vector rAdsTRII produced sTGFBRII that can abrogate TGF-B signaling while maintaining the replication potential of the virus, indicating that rAd-sTRII could be a potential anticancer agent. [Mol Cancer Ther 2006;5(2):367–73]