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

在本研究中，我们发现在小鼠Pro-B细胞系BAFB03细胞中，H-RAS的一种活性形式激活了α_4和α_6整合素，从而增强了细胞对纤维连接蛋白和层粘连蛋白的黏附。研究还发现，活性形式的H-RAS和c-Myc的功能协同导致α_4整合素的激活，诱导VLA4的反向受体VCAM1(α_4β_1)，下调α_6a整合素的表达，导致细胞的同嗜性聚集和对层粘连蛋白的粘附性丧失。此外，研究还表明，表达活性形式的H-RAS和c-Myc的BAF-B03细胞在裸鼠体内形成肿瘤，并表现出侵袭和转移。表达活性H-RAS和c-Myc的BAF-B03细胞层粘连蛋白结合丧失可能是肿瘤细胞从原发结节向外渗透的原因之一。研究H-RAS和c-Myc在调节细胞黏附分子的表达和/或活性方面的功能合作是否具有细胞类型特异性将是有意义的。在这项研究中，我们还发现，根据ICAM-1的表达水平，类风湿性关节炎(RA)患者的滑膜细胞可以分为两个功能不同的亚群。ICAM-1阳性细胞出现细胞周期停滞和细胞凋亡，而ICAM-1阴性细胞高效持续增殖。认为ICAM-1阴性的RA患者滑膜细胞可作为重要的治疗靶点。

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.