Altered Proteoglycan Gene Expression and Cancer

描述(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，浸润性癌周围核心蛋白粘附素的合成增加代表了一种对抗侵袭性肿瘤细胞的机制。这一工作假说是基于几个关键的观察结果：在大多数转化的细胞中，核心蛋白粘附素水平受到抑制，但在静止的细胞中显著增加。[B]有针对性地破坏核心蛋白聚糖的动物会发生自发的结肠癌，而具有核心蛋白聚糖和p53基因双重敲除的小鼠很快就会死于胸腺淋巴瘤，这表明核心蛋白聚糖的缺乏可能导致肿瘤的发生。[C]异位表达Decorin可在多种转化细胞中诱导深刻的细胞抑制效应。[D]核心蛋白聚糖与EGFR相互作用，导致其酪氨酸激酶活性显著减弱，从而导致生长抑制。[E]我们最近发现核心蛋白聚糖与Met受体酪氨酸激酶(RTK)直接相互作用，导致其在细胞内快速降解。这一证据为浸润性癌周围高水平的核心蛋白聚糖水平提供了一个机制解释，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，为核心蛋白聚糖的功能提供了另一层复杂性。在接下来的五年里，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PAN-RTK抑制剂的作用。2.确定Decorin/Met相互作用的精确结构要求；3.研究Decorin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坚定地确立核心蛋白在肿瘤发生中的功能作用，并阐明其作用机制。核心蛋白聚糖是一种新的Met受体拮抗剂，这种相互作用导致Met受体酪氨酸激酶和下游信号的明显减弱，这一发现首次证明了分泌的蛋白多糖与这一重要的信号转导途径相互作用。这些发现可能导致产生能够抑制Met受体功能的蛋白质模拟物。预期的结果可能为基础癌症研究开辟新的视角，并可能导致未来针对促进这种蛋白多糖表达的癌症预防和治疗方法，从而增加一种天然的肿瘤细胞生长抑制物。

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.