Absence of expression of the p16(INK4a) gene product is commonly observed in mesothelioma tumors and cell lines, while mild-type pRB expression is maintained. We have examined the biologic and potential therapeutic role of re-expressing p16(INK4a) gene product in mesothelioma cells and tumors. Following transduction with a p16(INK4a) expressing adenovirus (Adp16), over-expression of p16(INK4a) in mesothelioma cells resulted in cell cycle arrest, inhibition of pRB phosphorylation, diminished cell growth, and eventual death of the transduced cells. Expression of p16(INK4a) protein was accompanied by decreased expression of pRB as detected by immunoblot and immunohistochemistry. Experiments in mesothelioma xenografts demonstrated inhibition of tumor formation, tumor growth arrest and diminished tumor size and spread, p16(INK4a) gene product expression was also demonstrated in intraperitoneal xenografts of human mesothelioma cells. These results demonstrate that p16(INK4a) gene transfer may play a therapeutic role in the treatment of mesothelioma.
Bibliographical noteFunding Information:
We would like to thank Gloria Niehans and Pat Rene for their assistance in the processing of pathology specimens, and to Claudine Fasching for her assistance with flow cytometry. This work was supported in part by a Merit Grant from the Research Service of the Department of Veterans Affairs (RAK) and the National Institutes of Health -1 R01 CA 68245-01A1 (DTC).
- Tumor suppressor