Establishment of inflammatory and malignant tumor disease model mice based on abnormalities in adhesiveness of immune cells and its clinical application.

基于免疫细胞粘附异常的炎症及恶性肿瘤疾病小鼠模型的建立及其临床应用

• 批准号: 11557011
• 负责人: MINAMI Yasuhiro
• 金额: $ 7.17万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557011/
• 关键词: lymphocytes; proto-oncogenes; H-Ras; c-Myc; cell adhesion; Integrins; gene expression; anti-oncogene

In this study we found that in mouse pro-B cell line, BAF-B03 cells, an active form of H-Ras activates α_4 and α_6 integrins, thereby enhancing cell adhesiveness to fibronectin and laminin. It was also found that functional cooperation of an active form of H-Ras and c-Myc results in the activation of α_4 integrin, the induction of VCAM-1, a counter-receptor for VLA-4 (α_4β_1), and in the down-regulation of α_6a integrin, leading to homophilic cell aggregation and to a loss of cell adhesiveness to laminin. Furthermore, it was shown that BAF-B03 cells constitutively expressing an active form of H-Ras and c-Myc form tumor and exhibit invasion and metastasis when injected into nude mice. Loss of laminin binding of BAF-B03 cells expressing active H-Ras and c-Myc may contribute to infiltration of tumor cells from primary nodules. It would be of interest to examine whether or not functional cooperation of H-Ras and c-Myc in regulating the expression and/or activity of cell adhesion molecules is cell-type specific. In this study, we also showed that synovial cells from patients of Rheumatoid Arthritis (RA) can be separated into two functionally distinct subsets on the basis of the expression levels of ICAM-1. ICAM-1-positive cells exhibit cell cycle arrest and undergo apoptosis, while ICAM-1-negative cells proliferate efficiently and continuously. It is assumed that ICAM-1-negative synovial cells in RA patients can be an important therapeutic target.

本研究发现，在小鼠原B细胞系BAF-B 03细胞中，H-Ras的活性形式激活α_4和α_6整合素，从而增强细胞对纤连蛋白和层粘连蛋白的粘附。H-Ras与c-Myc的功能性协同作用可激活α_4整合素，诱导VLA-4（α_4β_1）的反受体VCAM-1的产生，并下调α_6 α整合素的表达，导致细胞聚集和层粘连蛋白对细胞的粘附功能丧失。此外，显示组成型表达活性形式的H-Ras和c-Myc的BAF-B 03细胞形成肿瘤，并且当注射到裸鼠中时表现出侵袭和转移。表达活性H-Ras和c-Myc的BAF-B 03细胞层粘连蛋白结合的丧失可能有助于肿瘤细胞从原发结节浸润。研究H-Ras和c-Myc在调节细胞粘附分子的表达和/或活性中的功能合作是否是细胞类型特异性的将是有意义的。在这项研究中，我们还表明，从风湿性关节炎（RA）患者的滑膜细胞可以分为两个功能不同的子集的基础上的ICAM-1的表达水平。ICAM-1阳性细胞表现出细胞周期停滞并经历凋亡，而ICAM-1阴性细胞有效且持续地增殖。据推测，ICAM-1阴性滑膜细胞在RA患者可以是一个重要的治疗目标。

项目成果

Tanaka,Y.,Nomi,M.,Minami,Y. 他6名: "ICAM-1 distinguishes functional heterogeneity of synovial cells in patients with rheumatoid arthritis : involvement of cell cycle machinery."Arthritis Rheum.. 43. 2513-2522 (2000)

Tanaka, Y.、Nomi, M.、Minami, Y. 和其他 6 人：“ICAM-1 区分类风湿性关节炎患者滑膜细胞的功能异质性：细胞周期机制的参与。”Arthritis Rheum.. 43. 2513-2522 (2000)

Fujimoto, H., Tanaka, Y., Liu, Z-J., Yagita H., Okumura, K., Kosugi, A., Morinobu, A., Yamamura, H., and Minami, Y.: "Down-regulation of α_6 integrin, an antioncogene product, by functional cooperation of H-Ras and c-Myc."Genes to Cells. (in press). (2001

Fujimoto, H.、Tanaka, Y.、Liu, Z-J.、Yagita H.、Okumura, K.、Kosugi, A.、Morinobu, A.、Yamamura, H. 和 Minami, Y.：“下调α_6 整联蛋白，一种抗癌基因产物，由 H-Ras 和 c-Myc 的功能合作产生。“基因到细胞。（印刷中）。（2001 年）

Takeuchi,S.: "mRor2 receptor tyrosine kinase is required for the heart development and limb formation."Genes to Cells. 5. 71-78 (2000)

Takeuchi,S.：“mRor2 受体酪氨酸激酶是心脏发育和肢体形成所必需的。”基因到细胞。

Liu,Z-J.,Tanaka,Y.,Minami,Y. 他8名: "A novel role for H-Ras in the regulation of VLA-4 integrin and VCAM-1 via c-Myc-dependent and-independent mechanisms."J.Immunol.. 163. 4901-4908 (1999)

Liu, Z-J.、Tanaka, Y.、Minami, Y. 和其他 8 人：“H-Ras 通过 c-Myc 依赖和独立机制调节 VLA-4 整合素和 VCAM-1 的新作用。”免疫学杂志.. 163. 4901-4908 (1999)

Tanaka, Y., Maruo, A., Fujii, K., Nomi, M., Nakamura, T., Eto, S., and Minami, Y.: "ICAM-1 discriminates functionally different populations of human osteoblasts : characteristic involvement of cell cycle regulators."J.Bone Mineral Res.. 15. 1912-1923 (200

Tanaka, Y.、Maruo, A.、Fujii, K.、Nomi, M.、Nakamura, T.、Eto, S. 和 Minami, Y.：“ICAM-1 区分功能不同的人类成骨细胞群体：特征参与