Asbestos fibers are carcinogenic and induce both lung cancers and mesotheliomas of the pleura and peritoneum in humans. The underlying cellular and molecular mechanisms in fiber carcinogenesis, however, are not clear. One of the main difficulties in studying mechanisms of fiber carcinogenesis is the lack of a suitable human cell model whereby the various tumorigenic stages can be dissected and the molecular changes associated with each stage examined. The recent availability of a well characterized human bronchial epithelial cell transformation model together with our preliminary data demonstrating that chrysotile fibers can induce malignant transformation of these cells form the basis for this proposal. Transformed cells progress through several sequential stages before becoming tumorigenic and producing progressively growing tumors in nude mice. In this revised application, Dr. Hei proposes to examine the underlying cellular and molecular alterations in fiber carcinogenesis using this human papillomavirus-immortalized human bronchial epithelial cell model. A series of cellular and molecular assays will be conducted using isolated clonal cell lines at each stage of the carcinogenic process to identify the necessary changes essential for fiber carcinogenesis. The proposal has 2 main objectives: The first is to establish an in vitro human epithelial cell transformation model for asbestos carcinogenesis using two independent, immortalized bronchial epithelial cell lines: and the second goal is to examine the molecular changes, particularly loss of tumor suppressor gene(s), associated with each stage of the carcinogenic process. A series of 5 specific aims are proposed to address 4 testable hypotheses. The BEP2D cells are anchorage dependent and do not form tumors in immunosuppressed host animals. Cytogenetic and molecular alterations at the gene level will be analyzed from tumors and intermediate transformation stages to provide a mechanistic basis for tumor induction by mineral fibers.
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