A large animal model to evaluate the effects of Hsp90 inhibitors for the treatment of lung adenocarcinoma.
Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The JSRV envelope glycoprotein (Env) functions as a dominant oncoprotein in vitro and in vivo. In order to develop the basis for the use of OPA as a lung cancer model, we screened a variety of signal transduction inhibitors for their ability to block transformation by the JSRV Env. Most inhibitors were not effective in blocking JSRV Env-induced transformation. On the contrary, various Hsp90 inhibitors efficiently blocked JSRV transformation. This phenomenon was at least partly due to Akt degradation, which is activated in JSRV-transformed cells. Hsp90 was found expressed in tumor cells of sheep with naturally occurring OPA. In addition, Hsp90 inhibitors specifically inhibited proliferation of immortalized and moreover primary cells derived from OPA tumors. Thus, OPA could be used as a large animal model for comprehensive studies investigating the effects of Hsp90 inhibitors in lung adenocarcinoma.
Varela
Mariana
M
Institute of Comparative Medicine, University of Glasgow Veterinary School, 464 Bearsden Road, Glasgow, G61 1QH, Scotland, UK.
Golder
Matthew
M
Archer
Fabienne
F
de las Heras
Marcelo
M
Leroux
Caroline
C
Palmarini
Massimo
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D000818:Animals; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D007150:Immunohistochemistry; D022141:Jaagsiekte sheep retrovirus; D008175:Lung Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D034561:Sheep, Domestic
D018841:HSP90 Heat-Shock Proteins