MOLECULAR MECHANISM FOR THE INDUCTION OF MESOTHELIOMA BY ASBESTOS

Occupational and environmental exposure to asbestos can lead to lung cancer and malignant mesothelioma. Mesothelioma is particularly difficult because it has a latency period of decades, treatment options are limited, and there is no cure. Mesothelioma originates in mesothelial cells that line the pleural and peritoneal cavities. In comparison to other cell types, human mesothelial cells are exquisitely sensitive to asbestos fibers. It has been suggested that binding of cell surface receptors (e.g. epidermal growth factor receptor; EGFR) to asbestos fibers triggers a cascading signal event, which initiates the mesothelioma. We used atomic force microscopy and molecular dynamic simulations to probe molecular bonds between EGFR and different minerals including asbestiform crocidolite and massive riebeckite. We discovered that asbestos elicits a unique force-signature when it binds to EGFR. By rupturing the mineral-EGFR bond at different loading rates, we were able to determine the bond lifetime for crocidolite and riebeckite. The crocidolite-EGFR bond has a lifetime of ~50 milliseconds, which is significantly shorter than the riebeckite-EGFR bond. This suggests that crocidolite would elicit a more potent biological response in vivo. Further, these measurements might also be used to classify asbestos minerals in terms of their actual biological activity as opposed to relying solely on size, which is the conventional measure for the carcinogenicity of asbestos.