CYCLOSPROINE AND LIVER CARCINOGENESIS

环脯氨酸与肝癌发生

• 批准号: 3198158
• 负责人: HISASHI SHINOZUKA
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3198158
• 关键词: cell growth regulation; cellular oncology; cyclosporines; cytotoxic T lymphocyte; drug carcinogenesis; hepatocellular carcinoma; immunocytochemistry; immunosuppressive; laboratory rat; liver cells; lymphocyte proliferation; neoplasm /cancer immunology; neoplastic cell; neoplastic growth; neoplastic process; preneoplastic state; transforming growth factors

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.

拟议研究的主要目标是阐明机制 控制肿瘤生长和进展的基础上，使用 肝癌和免疫抑制剂的实验模型， 环孢菌素（CsA）。 CsA 是目前最成功的方法之一 免疫抑制剂用于临床器官移植，但其用途 与多种恶性肿瘤的发生有关。此外， CsA对原发性肝肿瘤患者肝移植的疗效 由于受者体内肿瘤复发率很高，因此存在疑问 肝。我们的初步数据表明，免疫抑制剂量的 CsA 对小鼠表皮肿瘤进展产生深远影响 致癌作用和肝脏癌前病变的生长。 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 （坑细胞），但其功能尚未完全表征。可能的 肝脏非实质细胞参与控制正常和 恶性细胞生长已有报道。我们假设其中之一 CsA 调节肿瘤生长的潜在机制是通过 改变器官相关免疫调节细胞的功能。在 提案中，我们将进一步阐明 CsA 在此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 实质细胞增殖和对肝脏非实质细胞功能的影响 将研究包括凹坑细胞的细胞毒性。此外， 可能涉及肝脏非实质细胞，包括凹陷细胞 通过旁分泌生长调节来控制肝细胞生长 因子（即转化生长因子β）将被探索。这些 研究将为相关器官的作用提供新的见解 免疫调节细胞对肿瘤前细胞选择性生长的影响 关于肿瘤进展的过程。