The overall purpose of the proposed research is to demonstrate the gradual appearance of phenotypically altered cells during in vivo carcinogenesis of xeno-transplanted human respiratory tract epithelium. Using carcinogen- or genetically-altered human cells that repopulate de-epithelialized rat tracheas transplanted s.c. into nude mice, we will monitor their in vivo behavior and sensitivity to exposure or re-exposure to environmentally relevant carcinogens and promoters. The sensitivity of normal and altered cells to chemical agents will be demonstrated by histological detection of metaplastic-dysplastic lesions and histochemical markers of preneoplastic growth. Utilizing an in vivo - in vitro technique, these same tissues will be used to assess increased survival and resistance to terminal differentiation in selective culture media that do not permit growth of normal human tracheobronchial epithelial cells. Immortalized cell lines or cells with increased in vitro survival will be used for further in vivo experiments of xenotransplantation into de-epithelialized tracheas to assess their tumorigenicity and eventual increased sensitivity to chemical agents. Similarly and again to test in an alternative model the hypothesis that a prior history of exposure to chemical or biological carcinogens increases the sensitivity of human cells to promoters or chemical carcinogens, we will determine if immortalized tumorigenic and non-tumorigenic cells of tracheo-bronchial origin produced by viral infection (SV40- adenovirus) transfection (SV40, T antigen gene, B myc, c-Ha-ras, c-Ki-ras) or in vitro exposure to chemicals (TPA, MNNG, cigarette smoke condensate) exhibit progressive changes when exposed in vivo after repopulation in transplanted tracheas. These changes will be evaluated not only in tumorigenesis experiments, but also with histological sequential follow-up studies using histochemical markers and by monitoring the appearance of the late neoplastic or invasive-metastasizing phenotype, i.e., cell surface changes, (such as alterations in binding to laminin, fibronectin and lectins), demonstration of invasive behavior and colonization potential using biological assays.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Metabolic Pathology Study Section (MEP)
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Fox Chase Cancer Center
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Iizasa, T; Momiki, S; Bauer, B et al. (1993) Invasive tumors derived from xenotransplanted, immortalized human cells after in vivo exposure to chemical carcinogens. Carcinogenesis 14:1789-94
Klein-Szanto, A J; Iizasa, T; Momiki, S et al. (1992) A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells. Proc Natl Acad Sci U S A 89:6693-7
Caamano, J; DiRado, M; Iizasa, T et al. (1992) Partial suppression of tumorigenicity in a human lung cancer cell line transfected with Krev-1. Mol Carcinog 6:252-9
Zucker, S; Lysik, R M; Malik, M et al. (1992) Secretion of gelatinases and tissue inhibitors of metalloproteinases by human lung cancer cell lines and revertant cell lines: not an invariant correlation with metastasis. Int J Cancer 52:366-71
Caamano, J; Ruggeri, B; Momiki, S et al. (1991) Detection of p53 in primary lung tumors and nonsmall cell lung carcinoma cell lines. Am J Pathol 139:839-45
Momiki, S; Baba, M; Caamano, J et al. (1991) In vivo and in vitro invasiveness of human lung carcinoma cell lines. Invasion Metastasis 11:66-75
Klein-Szanto, A J (1991) The role of chemically induced epithelial hyperplasia in the development of human cancer. Prog Clin Biol Res 369:35-41
Bonfil, R D; Reddel, R R; Ura, H et al. (1989) Invasive and metastatic potential of a v-Ha-ras-transformed human bronchial epithelial cell line. J Natl Cancer Inst 81:587-94
Ura, H; Bonfil, R D; Reich, R et al. (1989) Expression of type IV collagenase and procollagen genes and its correlation with the tumorigenic, invasive, and metastatic abilities of oncogene-transformed human bronchial epithelial cells. Cancer Res 49:4615-21
Bonfil, R D; Momiki, S; Fridman, R et al. (1989) Enhancement of the invasive ability of a transformed human bronchial epithelial cell line by 12-O-tetradecanoyl-phorbol-13-acetate and diacylglycerol. Carcinogenesis 10:2335-8

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