An oncolytic adenovirus expressing soluble transforming growth factor-beta 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-beta type II receptor (sTGFbetaRII) offers a therapeutic advantage. We chose to target TGF-betas because they play a pivotal role in late-stage tumorigenesis by enhancing tumor invasion and metastasis. A sTGFbetaRII cDNA was cloned in conditionally replicating adenoviral vector rAd-sTRII and in a replication-deficient adenovirus Ad-sTRII. Infection of MDA-MB-231 breast cancer cells with rAd-sTRII or Ad-sTRII followed by Western blot analysis indicated the expression of diffused glycosylated forms of sTGFbetaRII that were also secreted into the extracellular medium. The secreted proteins were shown to bind with TGF-beta and antagonize TGF-beta-induced p38 mitogen-activated protein kinase activity. However, marked differences in the replication potential of rAd-sTRII and Ad-sTRII were observed in breast tumor cells. Infection of MDA-MB-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 rAd-sTRII produced sTGFbetaRII that can abrogate TGF-beta signaling while maintaining the replication potential of the virus, indicating that rAd-sTRII could be a potential anticancer agent.
Wang
Zhen-Guo
ZG
Laboratory of Gene Therapy, Evanston Northwestern Healthcare Research Institute, Evanston Hospital, Room B624, 2650 Ridge Avenue, Evanston, IL 60201, USA.
Zhao
Wenli
W
Ramachandra
Murali
M
Seth
Prem
P
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000628:therapy*; D006801:Humans; D050130:Oncolytic Virotherapy; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II