Mechanism of p120 downregulation in human cancer

描述（由申请人提供）：E-钙粘蛋白下调经常发生在癌症中，并且显然是转移的关键事件。有趣的是，最近对主要人类肿瘤类型的研究也揭示了pl 20的频繁下调，但pl 20下调的机制和后果尚不清楚。奇怪的是，可能代表p120缺陷的癌细胞系还没有被鉴定出来.此外，肿瘤中的p120下调在很大程度上被忽视了，因为直到最近才有令人信服的理由来关注这个问题。这一建议主要基于三个关键观察结果，其中两个是我们的初步数据。首先，p120是E-钙粘蛋白稳定性所必需的。其次，在最常见的人类癌症的重要子集中，p120表达经常下调或区域性缺失（例如，结肠、前列腺、肺、乳腺和其它）。第三，DN-钙粘蛋白在动物模型中强烈促进肿瘤进展和/或转移，并且可能通过隔离p120起作用。这些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-钙粘蛋白下调的主要事件。如果得到证实，这一概念将从根本上改变我们对大多数癌症类型中与转移转移有因果关系的事件的看法。到目前为止，我们还无法研究p120现象，因为我们无法充分模拟这种情况。小鼠肾异种移植模型提供了一种用于生长和维持人类肿瘤的新方法，其精确地表型复制它们最初来源的肿瘤。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p120和E-钙粘蛋白阴性，并可能获得其他。在目标1中，主要目的是使用该系统，并可能使用3D-基质胶培养，以确定在这些肿瘤中恢复p120表达是否足以拯救内源性E-钙粘蛋白（和上皮形态）。阳性结果将是极其重要的，因为这些异种移植物代表了大量类似处置的人类肿瘤，这些肿瘤无法以其他方式进行检测。在目标2中，我们提出进一步利用这些系统来鉴定肿瘤中p120下调的机制。这些概念可能会导致新的方法，旨在临床干预的水平上的肿瘤进展转移，在癌症生物学中最困难的问题之一。基质胶和异种移植模型可能是未来临床前研究的杰出模型，旨在了解如何重新启动p120（和E钙粘蛋白）。

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.