Development of molecular targeted therapy for malignant pleural mesothelioma

恶性胸膜间皮瘤分子靶向治疗的进展

基本信息

批准号：
17590792
负责人：
YANO Seiji
金额：
$ 2.24万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590792/
关键词：
malignant pleural mesothelioma orthotopic implantation model pleural effusion VEGF resistance to anticancer drugs EGF receptor MYO18B

项目摘要

Malignant pleural mesothelioma (MPM) grows aggressively with dissemination in the thoracic cavity and frequently produces malignant pleural effusion. MPM causes respiratory symptoms, including dyspnea, shortness of breath and chest pain, which thus severely limits the quality of life in patients with this disease. Since MPM is refractory to conventional chemotherapy and radiotherapy, the prognosis of MPM patients is extremely poor. To develop a novel therapeutic approach, the cellular and molecular pathogenesis of MPM should be clarified. For such purposes, we established a suitable animal model of MPM that shows patient-like tumor progression. A human MPM cell line (EHMES-10) inoculated orthotopically (thoracic cavity) into SCID mice produced highly vascularized thoracic tumors with pleural dissemination and bloody pleural effusions by 5 weeks.MYO18B, a novel member of the myosin family, is a tumor suppressor gene isolated from a homozygously deleted region at 22q12.1 in a lung cancer … More cell line. The inactivation of the MYO18B gene plays an important role in several malignant diseases. However, the role of MYO18B in the progression of MPM is still unknown. Six different human MPM cell lines were used in this study. Western blot revealed that none of the cell lines expressed a detectable level of MYO18B protein. One of the MPM cell lines, EHMES-10, was transfected with the MYO18B gene. We found that a restored expression of the MYO18B protein in EHMES-10 cells resulted in the inhibition of their anchorage-independent growth and motility in vitro. In addition, it also inhibited their ectopic (subcutaneous space) and orthotopic (thoracic cavity) growth in SCID mice, in association with an increased degree of cell-apoptosis. Furthermore, it also suppressed the production of bloody pleural effusion after orthotopic injection. These findings suggest that the restored expression of MYO18B may be a useful therapeutic strategy for the treatment of locally advanced MPM in humans. Less

恶性胸膜间皮瘤（MPM）在胸腔内扩散并侵袭性生长，经常产生恶性胸腔积液，导致呼吸困难、气短和胸痛等呼吸道症状，严重限制了患者的生活质量。由于MPM对常规化疗和放疗难以治愈，因此MPM患者的预后极差。为了开发一种新的治疗方法，研究MPM的细胞和分子发病机制。为此，我们建立了一种合适的 MPM 动物模型，将人类 MPM 细胞系 (EHMES-10) 原位（胸腔）接种到 SCID 小鼠中，产生具有胸膜的高度血管化的胸部肿瘤。 5周时出现播散和血性胸腔积液。MYO18B是肌球蛋白家族的新成员，是从纯合子中分离出的肿瘤抑制基因肺癌细胞系中 22q12.1 的缺失区域 MYO18B 基因的失活在多种恶性疾病中发挥着重要作用。然而，MYO18B 在 MPM 进展中的作用仍不清楚。本研究中使用的细胞系显示，没有一个细胞系表达可检测水平的 MYO18B 蛋白，其中一种 MPM 细胞系 EHMES-10 被转染。我们发现 EHMES-10 细胞中 MYO18B 蛋白的恢复表达导致其体外贴壁依赖性生长和运动受到抑制。此外，它还抑制了它们的异位（皮下间隙）和原位（皮下间隙）。 SCID 小鼠中胸腔的生长，与细胞凋亡程度的增加有关。此外，它还抑制了术后血性胸腔积液的产生。这些发现表明，MYO18B 表达的恢复可能是治疗人类局部晚期 MPM 的有效治疗策略。