Lung cancer is a devastating malignancy and the major cause of mortality among all cancers in both men and women with an abysmal less than 17% overall survival rate. My group has focused efforts on improving the understanding the process of lung carcinogenesis in order to be able to identify potential targets for intervention in this process. Our approach was to generate and characterize mice in which a gene first discovered by us in 1997 and called GPRC5A/RAI3 is deleted ("knocked out"). This gene was targeted because it is expressed primarily in normal lung tissue but in only about 50% of lung cancer cell lines. We found that such mice develop lung tumors suggesting that Gpcr5a gene may function as a tumor suppressor. An analysis of histological sections prepared from tumors that had developed in the Gpcr5a knockout mice revealed that most of the tumors were lung adenomas (premalignant lesions) but seven of the specimens from 41 knockout (-/-) mice were found to contain malignant tumors. No malignant tumors were detected in either the heterozygous (+/-) or the wild type (+/+) mice. In addition, we detected macrophage pneumonia in 37% of the knockout (-/-) mice compared to less than 10% in the (+/-) and (+/+) mice. Based on this finding, we raised the hypothesis that inflammation might play a role in enhancing tumor development in the knockout mice. We also obtained clues about some possible roles of the protein encoded by the Gpcr5a gene by expressing the gene in lung and colon cancer cells. Cells that over-expressed GPCR5A gene exhibited suppression of the activation of a survival mechanism mediated by a gene called NF-kB (nuclear factor kappa B). This finding suggests that the loss of expression of GPCR5A in human lung tumors may enhance the cancer promoting effects of inflammation. Another possible function may be related to control of cell growth and survival because epithelial cells from the +/+ mice did not survive in culture conditions beyond several passages and died, in contrast, the cells from -/- mouse exhibited properties of immortal cells and have survived already 6 months in culture and are still growing well. Thus, we have identified a new tumor suppressor gene and obtained some clues about its function.

return to top