CYCLOSPROINE AND LIVER CARCINOGENESIS

拟议研究的主要目标是澄清这些机制 控制肿瘤生长和进展的基础上，使用 肝癌发生的实验模型和一种免疫抑制剂， 环孢素(CsA)。CSA目前是最成功的 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。此外， 环孢素A在原发性肝肿瘤患者肝移植中的应用 因为接受者肿瘤复发率很高，所以有问题 肝脏。我们的初步数据显示，免疫抑制剂量的环孢素A 对小鼠表皮的肿瘤进展有深远的影响 癌症的发生和肝脏癌前病变的生长。 皮肤和肝脏都含有免疫相关细胞，Thy1 表皮树突状细胞与肝脏相关大颗粒淋巴细胞 (坑细胞)，但其功能尚未完全确定。可能的 肝脏非实质细胞参与正常对照和正常对照的研究 已有恶性细胞生长的报道。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功能改变。在 建议，我们将进一步澄清CsA在这一过程中的生物学作用 肝癌发生过程中肿瘤进展的研究。环孢素A对肝脏的影响 肝实质细胞增殖及其对非实质细胞功能的影响 包括PIT细胞的细胞毒性将被调查。此外, 包括凹陷细胞在内的肝脏非实质细胞可能参与了 旁分泌调控对肝细胞生长的调控 将探索各种因素(即转化生长因子β)。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病变细胞选择性生长的影响 关于肿瘤进展过程的研究。

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.