We have found that when carcinogen-altered preneoplastic and neoplastic tracheal epithelial cells (TEC) and normal TEC are cocultured in vivo in devitalized tracheal grafts the normal cells markedly reduce the survival of the altered cells. A similar effect was observed in culture. The inhibition in culture is at least partially due to the presence of an inhibitor present in normal TEC conditioned medium (CM). Inhibitory TEC-CM has been found to contain transforming growth factor type Beta. It is not clear, however, whether the inhibition of altered TEC by normal TEC in vivo is associated with the production of TGF-Beta. The proposed experiments are intended to ultimately determine the relevance, if any, of TGF-Beta/GI detected in TEC-CM to the control of growth and differentiation in the intact trachea. Similarly, we will investigate the relevance of changes in production or sensitivity to TGF-Beta/GI observed during neoplastic progression to the loss of growth control characteristic of neoplastic disease. Using combinations of in vivo, in vivo-in vitro, and in vitro techniques developed as part of the rat tracheal cell model we will investigate: (1) influence of proliferation and differentiation on TGF-Beta/GI production by normal epithelial cells; (2) effects of carcinogen-exposure on sensitivity to inhibition by, and production of TGF-Beta/GI; (3) changes in proliferation and differentiation induced by TGF-Beta in sensitive target cells; (4) define cofactor requirements for TGF-Beta/GI inhibition of TEC; and (5) determine the influence of cell shape on TGF-Beta/GI inhibition of TEC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemical Pathology Study Section (CPA)
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Lockheed Martin Energy Systems, Inc.
Oak Ridge
United States
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Chang, G W; Terzaghi-Howe, M (1998) Multiple changes in gene expression are associated with normal cell-induced modulation of the neoplastic phenotype. Cancer Res 58:4445-52
Terzaghi-Howe, M; Chang, G W; Popp, D (1997) Emergence of undifferentiated rat tracheal cell carcinomas, but not squamous cell carcinomas, is associated with a loss of expression of E-cadherin and of gap junction communication. Carcinogenesis 18:2043-50
Terzaghi-Howe, M (1993) Factors regulating the emergence of spontaneous and X-ray-induced variants in primary rat tracheal epithelial cell cultures. In Vitro Cell Dev Biol 29A:120-6
Ford, J R; Terzaghi-Howe, M (1992) Characteristics of magnetically separated rat tracheal epithelial cell populations. Am J Physiol 263:L568-74
Terzaghi-Howe, M (1990) Interactions between cell populations influence expression of the transformed phenotype in irradiated rat tracheal epithelial cells. Radiat Res 121:242-7
Terzaghi-Howe, M (1989) Induction of preneoplastic alterations by X rays and neutrons in exposed rat tracheas and isolated tracheal epithelial cells. Radiat Res 120:352-63
Terzaghi-Howe, M (1989) Inhibitor production by normal rat tracheal epithelial cells influences the frequency of spontaneous and X-ray-induced enhanced growth variants. Carcinogenesis 10:967-71
Terzaghi-Howe, M (1989) Changes in response to, and production of, transforming growth factor type beta during neoplastic progression in cultured rat tracheal epithelial cells. Carcinogenesis 10:973-80
Niyogi, K; Kennel, S J; Terzaghi-Howe, M (1987) Analysis of differentiation antigens on normal and carcinogen-altered rat epithelial cells in vivo and in culture. Differentiation 34:40-9
Terzaghi-Howe, M (1987) Inhibition of carcinogen-altered rat tracheal epithelial cell proliferation by normal epithelial cells in vivo. Carcinogenesis 8:145-50

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