Mechanism of p120 downregulation in human cancer

人类癌症中 p120 下调的机制

• 批准号: 6856420
• 负责人: ALBERT B REYNOLDS
• 金额: $ 13.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856420
• 关键词: cadherins; immunocytochemistry; kidney transplantation; laboratory mouse; metastasis; neoplasm /cancer genetics; neoplastic process; technology /technique development; tumor suppressor genes; xenotransplantation

DESCRIPTION (provided by applicant): E-cadherin downregulation occurs frequently in cancer and is clearly a pivotal event in the transition to metastasis. Interestingly, recent studies of the major human tumor types also reveal frequent downregulation ofpl20, but the mechanism and consequences of pl20 downregulaton are unknown. Paradoxically, cancer cell lines that might represent the p 120-deficient condition have not been identified. Moreover, p 120 downregulation in tumors has been largely ignored because until recently there was no compelling reason to focus on the issue. This proposal is based primarily on three key observations, two of which constitute our preliminary data. First, p120 is required for E-cadherin stability. Second, p120 expression is frequently downregulated or regionally absent in a significant subset of the most common human cancers (e.g., colon, prostate, lung, breast, and others). Third, DN-cadherins strongly promote tumor progression and/or metastasis in animal models, and probably act via sequestering p 120. The data provides compelling evidence that p120 downregulation could be the main event leading to E-cadherin downregulation in a large number of tumors. If validated, this concept will radically change how we think about an event that is causally linked to the transition to metastasis in most carcinoma types. Until now, we have not been able to study the p120 phenomenon because we could not adequately model the condition. The mouse renal xenograft model provides a novel method for growing and maintaining human tumors that accurately phenocopy the tumors from which they were originally derived. Importantly, we now have two xenografts (prostate and lung) that are almost completely p120 and E-cadherin negative, and probable access to others. In aim 1, the major objective is to use this system, and possibly 3D-matrigel cultures, to determine whether restoring p 120 expression in these tumors is sufficient to rescue endogenous E-cadherin (and epithelial morphology). A positive result would be extremely significant because these xenografts represent a huge number of similarly disposed human tumors that are not otherwise accessible for testing. In aim 2, we propose to take further advantage of these systems to identify the mechanism of pl20 downregulation in tumors. These concepts may lead to novel approaches aimed at clinical intervention at the level of tumor progression to metastasis, one of the most difficult issues in cancer biology. The matrigel and xenograft models could be outstanding models for future preclinical studies aimed at learning how to turn p 120 (and Ecadherin) back on.

描述（由申请人提供）：E-钙粘蛋白下调经常发生在癌症中，显然是转移过渡的关键事件。有趣的是，对主要人类肿瘤类型的最新研究也表明PLPL20的下调经常下调，但是PL20下调的机理和后果尚不清楚。矛盾的是，尚未确定可能代表P 120缺陷疾病的癌细胞系。此外，肿瘤中的P 120下调在很大程度上被忽略了，因为直到最近才有令人信服的理由专注于这个问题。该提案主要基于三个关键观察，其中两个构成了我们的初步数据。首先，E-钙粘蛋白稳定性需要P120。其次，在最常见的人类癌症（例如结肠，前列腺，肺，乳房等）中，P120表达经常被下调或区域性不存在。第三，DN-核蛋白在动物模型中强烈促进肿瘤的进展和/或转移，并且可能通过隔离P 120起作用。数据提供了令人信服的证据，表明P120下调可能是导致大量肿瘤中e-钙粘着蛋白下调的主要事件。如果经过验证，这个概念将从根本上改变我们对与大多数癌类型转移的因果关系相关的事件的看法。到目前为止，我们还无法研究P120现象，因为我们无法充分建模这种情况。小鼠肾异种移植模型提供了一种新的方法，用于生长和维持人类肿瘤，以准确地表达其最初衍生的肿瘤。重要的是，我们现在有两个异种移植物（前列腺和肺）几乎完全是P120和E-钙粘着蛋白负的，并且可能与他人访问。在AIM 1中，主要目的是使用该系统，甚至可能是3D-Matrigel培养物，以确定在这些肿瘤中恢复P 120的表达是否足以挽救内源性E-钙粘蛋白（和上皮形态）。积极的结果将非常重要，因为这些异种移植物代表了许多类似处置的人类肿瘤，这些肿瘤原本无法进行测试。在AIM 2中，我们建议进一步利用这些系统，以确定肿瘤中PL20下调的机理。这些概念可能导致旨在以肿瘤发展为转移水平的临床干预的新方法，这是癌症生物学中最困难的问题之一。 Matrigel和异种移植模型可能是未来临床前研究的杰出模型，旨在学习如何将P 120（和Ecadherin）重新开出。