The Wnt Pathway in Malignant Mesothelioma

恶性间皮瘤中的 Wnt 通路

• 批准号: 6874585
• 负责人: DAVID M. JABLONS
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874585
• 关键词: DNA methylation; apoptosis; athymic mouse; cadherins; cell line; clinical research; gene expression; human tissue; immunocytochemistry; in situ hybridization; mesothelioma; molecular oncology; monoclonal antibody; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplasm /cancer transplantation; neoplastic process; oncoproteins; protein protein interaction; protooncogene; small interfering RNA; transcription factor; transfection; xenotransplantation

DESCRIPTION (provided by applicant): The long-term objective for this proposal is the elucidation of molecular mechanisms for the wingless-type (Wnt)/beta-catenin signaling pathway in malignant mesothelioma (MM) and the development of molecular therapies for this malignancy. Mesothelioma is a relatively uncommon but inexorably fatal tumor, affecting about 3000 new patients in the United States annually. Despite advances in cancer treatment, the medium survival rate remains low and most patients die within two years after diagnosis. The pathogenesis of mesothelioma remains poorly understood and the molecular mechanism by which mesothelial cells undergo neoplastic transformation is largely unknown. For this proposal, we will test the hypothesis that aberrant activation of Wnt signaling pathway plays important roles in malignant mesothelioma. Preliminary data from our laboratory showed that the Wnt signaling pathway is activated in MM as evidenced by increased cytosolic/nuclear beta-catenin, and c-Myc, the two downstream target genes, downregulation of the potential endogenous inhibitor secreted frizzled related protein (SFRP2), and an increased phosphorylation of the Wnt pathway mediator dishevelled protein (Dvl-3). These observations have not been described previously nor elucidated in MM. The specific Aims for this application are 1) to confirm that Wnt signaling pathway is activated in mesothelioma in a large number of primary tumor samples: 2) to investigate molecular mechanisms of Wnt signaling activation in mesothelioma. initially by examining the role of SFRP2 and Dvl-3; 3) to investigate whether a Wnt-1 signaling is a survival factor, thus inhibits apoptosis, in mesothelioma using an anti-Wnt-1 ligand monoclonal antibody and siRNA; and 4) to develop molecular therapies by targeting the Wnt-1 ligand with monoclonal antibody in vivo. Recent information about the Wnt signaling pathway reveals its vital importance in both embryogenesis and oncogenesis. Our study aims to reveals its role in malignant mesothelioma, and to add significantly to the emerging knowledge about the Wnt pathway in cancer in general.

描述（由申请人提供）：该提案的长期目标是阐明恶性间皮瘤（MM）中无翼型（Wnt）/β-连环蛋白信号通路的分子机制以及开发针对这种恶性肿瘤的分子疗法。间皮瘤是一种相对罕见但不可避免的致命肿瘤，每年影响美国约 3000 名新患者。尽管癌症治疗取得了进展，但中等生存率仍然很低，大多数患者在诊断后两年内死亡。间皮瘤的发病机制仍然知之甚少，间皮细胞发生肿瘤转化的分子机制也很大程度上未知。对于这个提议，我们将检验 Wnt 信号通路的异常激活在恶性间皮瘤中发挥重要作用的假设。我们实验室的初步数据表明，Wnt 信号通路在 MM 中被激活，表现为胞质/核 β-catenin 和 c-Myc（两个下游靶基因）的增加，潜在的内源性抑制剂分泌型卷曲相关蛋白 (SFRP2) 的下调，以及 Wnt 通路介质蓬乱蛋白 (Dvl-3) 的磷酸化增加。这些观察结果以前没有在 MM 中描述过或阐明。本申请的具体目的是1）在大量原发性肿瘤样本中证实Wnt信号通路在间皮瘤中被激活：2）研究间皮瘤中Wnt信号激活的分子机制。首先检查 SFRP2 和 Dvl-3 的作用； 3)使用抗Wnt-1配体单克隆抗体和siRNA研究间皮瘤中Wnt-1信号传导是否是生存因子，从而抑制细胞凋亡； 4）通过体内单克隆抗体靶向Wnt-1配体来开发分子疗法。关于 Wnt 信号通路的最新信息揭示了其在胚胎发生和肿瘤发生中的至关重要性。我们的研究旨在揭示其在恶性间皮瘤中的作用，并显着增加关于癌症中 Wnt 通路的新兴知识。