Mechanism of p120 downregulation in human cancer

描述(由申请人提供)：E-钙粘素下调在癌症中经常发生，显然是转移到转移过程中的关键事件。有趣的是，最近对人类主要肿瘤类型的研究也揭示了PL20的频繁下调，但PL20下调的机制和后果尚不清楚。矛盾的是，可能代表p120缺陷状态的癌细胞株还没有被鉴定出来。此外，p120在肿瘤中的下调在很大程度上被忽视了，因为直到最近，还没有令人信服的理由来关注这个问题。这项建议主要基于三个关键观察结果，其中两个构成了我们的初步数据。首先，p120是E-钙粘附素稳定所必需的。其次，在人类最常见的癌症(如结肠癌、前列腺癌、肺癌、乳腺癌和其他癌症)中，p120的表达经常下调或区域性缺失。第三，在动物模型中，dN-钙粘附素强烈促进肿瘤进展和/或转移，并可能通过隔离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-钙粘素下调的主要事件。如果得到验证，这个概念将从根本上改变我们对与大多数癌症类型的转移有因果联系的事件的看法。到目前为止，我们还不能研究p120现象，因为我们不能对这种情况进行充分的建模。小鼠异种肾移植模型为生长和维持人类肿瘤提供了一种新的方法，可以准确地复制肿瘤的原始来源。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-钙粘素阴性的，并可能接触到其他移植物。在目标1中，主要目的是使用这个系统，可能还有3D-Matrigel培养，以确定恢复这些肿瘤中p120的表达是否足以挽救内源性E-钙粘附素(和上皮形态)。一个积极的结果将是极其重要的，因为这些异种移植代表了大量处理相似的人类肿瘤，否则无法进行检测。在目标2中，我们建议进一步利用这些系统来确定PL20在肿瘤中下调的机制。这些概念可能导致针对肿瘤进展到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优秀模型，旨在学习如何重新启动p120(和Ecadherin)。

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.