Altered Proteoglycan Gene Expression and Cancer

描述（由申请人提供）：本提案的长期目标是阐明核心蛋白聚糖在控制细胞增殖中的作用机制。 我们的中心假设是，在浸润性癌周围核心蛋白聚糖的合成增加代表了一种对抗侵袭性肿瘤细胞的机制。 这个工作假设是基于几个关键的观察结果：[a]核心蛋白聚糖水平在大多数转化细胞中受到抑制，但在静止细胞中显着增加。 [b]具有核心蛋白聚糖靶向破坏的动物发展自发性结肠肿瘤，并且具有核心蛋白聚糖和p53基因双敲除的小鼠迅速死于胸腺淋巴瘤，表明缺乏核心蛋白聚糖允许肿瘤发生。 [c]核心蛋白聚糖的异位表达在多种转化细胞中诱导显著的细胞生长抑制作用。 [d]核心蛋白聚糖与EGFR相互作用并导致其酪氨酸激酶活性的显著减弱，从而导致生长抑制。 [e]我们最近发现，核心蛋白聚糖直接与Met受体酪氨酸激酶（RTK）相互作用，导致其快速细胞内降解。 这些证据为浸润性癌周围核心蛋白聚糖水平升高提供了机制解释，并表明核心蛋白聚糖可能作为富含RTK的肿瘤细胞的天然拮抗剂发挥作用，为核心蛋白聚糖功能提供了另一层复杂性。 在未来五年，我们计划：1。破译核心蛋白聚糖下调Met受体途径的作用机制及其作为泛RTK抑制剂的作用。2.确定核心蛋白聚糖/Met相互作用的精确结构要求，以及3.研究核心蛋白聚糖作为一种抗肿瘤和抗血管生成因子的体内功能。 这些协调一致的研究路线应该牢固地建立核心蛋白聚糖在肿瘤发生中的功能作用，并阐明其作用机制。 核心蛋白聚糖是Met受体的新型拮抗剂，并且这种相互作用导致Met受体酪氨酸激酶和下游信号传导的明显减弱，这一发现首次证明了分泌的蛋白聚糖与这种重要的信号转导途径相互作用。 这些发现可能导致能够抑制Met受体功能的蛋白质模拟物的产生。 预期的结果可能为基础癌症研究开辟新的前景，并可能导致未来的癌症预防和治疗方法，旨在促进这种蛋白聚糖的表达，从而增加肿瘤细胞生长的天然抑制剂。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the mechanism of action of decorin in controlling cell proliferation. Our central hypothesis is that the augmented synthesis of decorin around invasive carcinomas represents a mechanism to counteract the invading neoplastic cells. This working hypothesis is based on several key observations: [a] Decorin levels are suppressed in most transformed cells, but markedly increased in quiescent cells. [b] Animals harboring a targeted disruption of decorin develop spontaneous colon tumors and mice with a double knock out of decorin and p53 genes die rapidly of thymic lymphomas, indicating that lack of decorin is permissive for tumorigenesis. [c] Ectopic expression of decorin induces profound cytostatic effects in a wide variety of transformed cells. [d] Decorin interacts with the EGFR and causes a profound attenuation of its tyrosine kinase activity, thereby leading to growth inhibition. [e] We have recently discovered that decorin interacts directly with the Met receptor tyrosine kinase (RTK) causing its rapid intracellular degradation. This body of evidence offers a mechanistic explanation for the heightened decorin levels around invasive carcinomas and indicates that decorin may function as a natural antagonist of neoplastic cells enriched in RTKs, providing yet another layer of complexity to decorin function. Over the next five years we plan to: 1. Decipher the mechanism of action of decorin in downregulating the Met receptor pathway and its role as a pan-RTK inhibitor. 2. Determine the precise structural requirements for decorin/Met interaction, and 3. Investigate the in vivo function of decorin as an anti-oncogenic and anti-angiogenic factor. These concerted research lines should firmly establish the functional roles of decorin in tumorigenesis and shed light on its mechanism of action. The discovery that decorin is a novel antagonist of the Met receptor and that this interaction leads to an overt attenuation of the Met receptor tyrosine kinase and downstream signaling provides the first demonstration of a secreted proteoglycan interacting with this important signal transducing pathway. These findings could lead to the generation of protein mimetics capable of suppressing Met receptor function. The expected results could open novel perspectives for basic cancer research, and could lead to future approaches of cancer prevention and treatment directed at boosting the expression of this proteoglycan, thereby increasing a natural inhibitor of tumor cell growth.