CYCLOSPROINE AND LIVER CARCINOGENESIS

这项研究的主要目的是阐明 在控制肿瘤生长和进展的基础上， 肝癌发生的实验模型和免疫抑制剂， 环孢素（CsA）。CsA是目前最成功的 免疫抑制剂用于临床器官移植，但其用途是 与各种恶性肿瘤的发展有关。此夕h 环孢素A对原发性肝肿瘤患者肝移植疗效观察 由于接受者肿瘤复发率高， 肝脏我们的初步数据表明免疫抑制剂量的CsA 对小鼠表皮中的肿瘤进展有深远的影响， 癌发生和对肝脏中癌前病变的生长的影响。 皮肤和肝脏都含有免疫相关细胞Thy 1+ 表皮树突状细胞和肝相关大颗粒淋巴细胞 (Pit细胞），但其功能尚未完全表征。可能 肝非实质细胞参与正常和 已经报道了恶性细胞生长。我们假设其中一个 CsA调节肿瘤生长的潜在机制是通过 器官相关免疫调节细胞的功能改变。在 建议，我们将进一步阐明CsA在该过程中的生物学作用 肝癌发生过程中的肿瘤进展。CsA对肝脏的影响 实质细胞增殖和肝非实质细胞功能 包括小窝细胞的细胞毒性。此外，本发明还提供了一种方法， 可能涉及肝脏非实质细胞，包括小凹细胞， 通过旁分泌调节肝细胞生长 转化生长因子（transforming growth factor beta）。这些 研究将为相关器官的作用提供新的见解， 免疫调节细胞对癌前细胞选择性生长的影响， 肿瘤进展的过程。

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.