Gene Expression Analysis for Asbestos-Induced Lung Cancer

Brooke T. Mossman, Ph.D.
University of Vermont College of Medicine
R01ES09213

Background: Asbestos, the naturally occurring group of mineral fibers once used extensively as an insulator in many domestic and industrial settings, has been known for decades to cause a rare form of lung cancer in exposed workers. The cancer originates in the mesothelial lung cells and is therefore known as mesothelioma. Mesothelioma is difficult to treat and is generally known to have a poor prognosis. Even though the carcinogenic potential for the crocidolite form of the fiber is well known, the molecular and cellular mechanisms influenced by exposure and leading to malignancy have not been well characterized. In many different cell culture systems, asbestos fibers have been shown to have a variety of effects in the multistage process of tumorigenesis including DNA damage by causing oxidative lesions and base deletions, hyperplasia, and changes in normal gene expression.

Advance: Using the increasingly popular tool of microarray gene expression analysis, NIEHS-supported researchers at the University of Vermont sought to better characterize subsets of genes that were either "turned on" or "turned off" in rat mesothelial cells after exposure to acute asbestos and also in active mesothelioma tumors. These studies were the first of their kind and demonstrated that increased expression of a gene leading to the development of cancer, a proto-oncogene, known as fra1 was linked to the expression of two other genes, cmet and cd44, which have been linked to migration and invasiveness of tumor cells.

Implication: Even though asbestos has been banned in the United States, cases of malignant mesothelioma have increased at an alarming rate over the years. Currently there are over 3,000 recorded cases of persons that are diagnosed with malignant mesothelioma each year in the United States alone. The studies highlighted here suggest that inhibition of fra-1 signaling pathways may be an effective strategy for treating malignant mesothelioma. The ability to modify the expression of critical genes involved in the spreading of tumors by inhibiting fra1 expression could be used as a therapeutic approach to stop the chain of events in tumor progression.

Citation: Ramos-Nino ME, Scapoli L, Martinelli M, Land S, Mossman BT. Microarray analysis and RNA silencing link fra-1 to cd44 and c-met expression in mesothelioma. Cancer Res. 2003 Jul 1;63(13):3539-45.