Mechanism of p120 downregulation in human cancer

描述（由申请人提供）：e -钙粘蛋白下调在癌症中经常发生，并且显然是转移过程中的关键事件。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缺陷状况的癌细胞系尚未被确定。此外，肿瘤中的p120下调在很大程度上被忽视了，因为直到最近还没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，其中两个构成了我们的初步数据。首先，p120是E-cadherin稳定性所必需的。其次，在大多数常见的人类癌症（如结肠癌、前列腺癌、肺癌、乳腺癌等）中，p120的表达经常下调或局部缺失。第三，在动物模型中，dn -钙粘蛋白强烈促进肿瘤进展和/或转移，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-cadherin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的转移有因果关系的事件的看法。到目前为止，我们还不能研究p120现象，因为我们不能充分地模拟这种情况。小鼠肾脏异种移植模型为人类肿瘤的生长和维持提供了一种新的方法，可以准确地反映它们最初产生的肿瘤的表型。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-cadherin阴性，并且可能进入其他。在目的1中，主要目的是使用该系统，可能还有3d基质培养，来确定恢复p120在这些肿瘤中的表达是否足以挽救内源性e -钙粘蛋白（和上皮形态）。阳性结果将是非常重要的，因为这些异种移植物代表了大量类似处理的人类肿瘤，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肿瘤中pl20下调的机制。这些概念可能会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。基质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.