M. D. Anderson Researchers Identify Tumor-Suppressor Gene for Lung Cancer
The GPRC5A gene, which is under-expressed in human lung cancer cells, suppresses lung tumors in mouse models and could provide a key to attacking lung cancer in humans, researchers at The University of Texas M. D. Anderson Cancer Center report in the Nov. 21 edition of The Journal of the National Cancer Institute.
The study found that mice with both of their GPRC5A genes suppressed developed normally until their second year of life, when 76% developed precancerous lesions called adenomas in their lungs and another 17% developed malignancies called adenocarcinomas. Only 10% of mice with both GPRC5A genes intact developed adenomas, and only 11% with one working version of the gene. None of the mice in the latter two groups developed lung cancer.
"In humans, lung adenocarcinomas are the most common type of lung cancer and the major cause of death from this disease," says senior author Reuben Lotan, Ph.D., professor in M. D. Anderson's Department of Thoracic/ Head and Neck Medical Oncology. "Further study substantiating the role of the GPRC5A gene in human lung cancer could lead to the development of novel approaches for lung cancer prevention, diagnosis and treatment."
Lung cancer is the leading cause of deaths by cancer, killing 160,000 Americans annually.
Lotan and colleagues earlier had shown that Gprc5a protein is detected in the lungs more than in any other tissue and that it is underexpressed in human non-small cell lung cancer and in head and neck squamous cell carcinoma.
The mouse model experiments were designed to follow-up on these early clues of a tumor-suppressing role for the gene. Loss of a tumor-suppressor gene product such as Gprc5a protein is an important step in cancer development.
The team also found that the tumors generated in the mice without the genes lacked mutations to the K-Ras gene, a common oncogene that fuels cancer growth. "This may be important because the carcinogenesis pathway observed in our model may be relevant to the more than 65% of human non-small cell lung cancers that don't have K-Ras mutations," Lotan says.
Expression of the gene was compared in 18 pairs of human non-small cell lung cancer and adjacent normal tissue. In 11 cases, or 61%, the tumors had lower levels of GPRC5A messenger RNA than did the nearby normal tissue. Two had higher levels of expression in the tumor and one pair had similar levels in both tissues. Four had no expression in either sample.
Next, the team used gene expression profiling with a microarray to compare 186 lung tumors to 17 normal control tissues. The four tumor types all had a fraction of the GPRC5A gene expression shown in the normal cells: adenocarcinoma 46.2%; squamous cell carcinoma at 7.5%; small-cell lung cancer at 5.3%; and carcinoid at 1.8%.
Finally, they inserted the GPRC5A gene back into lung cancer cell lines in a laboratory experiment, suppressing colony formation of human lung cancer cells by 91% in two cell lines.
"These findings suggest that GPRC5A can suppress lung cancer development in humans as well as mice," Lotan says.
With Lotan and lead author, Qingguo Tao, M.D., Ph.D., other M. D. Anderson co-authors are Junya Fujimoto M.D., Ph.D., Taoyan Men, D.V.M., Xiaofeng Ye, M.Sc., Jiong Deng, Ph.D, Ludovic Lacroix, Ph.D., Li Mao, M.D., Dafna Lotan, M.Sc., all of the Department of Thoracic/Head and Neck Medical Oncology; Carolyn S. Van Pelt, Ph.D., D.V.M., of the Department of Veterinary Medicine and Surgery; J. Jack Lee, Ph.D., of the Department of Biostatistics; and co-author John L. Clifford, Ph.D ., of the Department of Clinical Cancer Prevention now at Louisiana State University.
The work reported in this article was supported by the Samuel Waxman Cancer Research Foundation; Irving and Nadine Mansfield and Robert David Levitt Cancer Research Chair; and Cancer Center Support Grant of M. D. Anderson from the National Institutes of Health. 11/13/07