The major objective of the proposed study is to clarify the mechanisms underlying the control of tumor growth and progression, using the experimental models of liver carcinogenesis and an immunosuppressant, cyclosporine (CsA). CsA is presently one of the most successful immunosuppressants used in clinical organ transplantation, but its use is associated with the development of various malignancies. Further, the efficacy of CsA on liver transplants of patients with primary liver tumors is questionable because of a high rate of recurrence of tumors in recipient liver. Our preliminary data indicated that an immunosuppressive dose of CsA had profound effects on tumor progression in murine epidermal carcinogenesis and on the growth of preneoplastic lesions in the liver. Both the skin and the liver contain immunologically relevant cells, Thy 1+ epidermal dendritic cells and liver associated large granular lymphocytes (Pit cells ) , but their functions are not fully characterized. Possible involvement of liver non parenchymal cells in control of normal and malignant cell growth has been reported. We postulate that one of the underlying mechanisms of CsA-modulation of tumor growth is mediated through altered functions of the organ associated immunoregulatory cells. In the proposal, we will clarify further biological roles of CsA on the process of tumor progression in liver carcinogenesis. Effects of CsA on liver parenchymal cell proliferation and on liver non parenchymal cell functions including the cytotoxicity of pit cells will be investigated. In addition, possible involvement of liver non parenchymal cells including pit cells in the control of liver cell growth via paracrine regulations of growth factors (i.e. transforming growth factor beta) will be explored. These studies will provide a new insight into the roles of organ associated immunoregulatory cells on the selective growth of preneoplastic cells and on the process of tumor progression.
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