ROLE OF THE UROKINASE RECEPTOR IN INVASIVE COLON CANCER

结肠癌患者的高死亡率总是反映出 疾病传播到次级器官。对这一概念的理解 强调疾病这一阶段的机制最终可能， 导致旨在对抗肿瘤扩散的治疗策略。这个 肿瘤细胞降解周围细胞外基质的能力， 通过水解机制，代表了第一步 转移。纤溶酶原激活物(PA)，尿激酶(u-PA)，已被 通过其转换惰性物质的能力与肿瘤细胞的侵袭有关 纤溶酶原转化为丝氨酸蛋白酶纤溶酶，分解关键成分 细胞外基质，包括层粘连蛋白和IV型胶原。U-PA 可以与细胞上的特定受体结合，而不是向下- 调节，从而使PA集中在肿瘤细胞表面。 受体结合的u-PA激活纤溶酶原的速度快于液体- U-PA期。在特定的目标#1中，该结合位点在体外的作用 体内侵袭将通过基因转导研究和 通过利用一种与细胞表面竞争的可溶性受体 U-PA结合的受体。多项研究表明，内源性 U-PA抑制物可抑制液相纤溶酶原激活物。 然而，受体结合的u-PA对这些抑制剂的敏感性 目前还不清楚。在具体目标#2中， 内源性u-PA抑制物通过受体阻断纤溶酶原激活 结肠癌的u-PA结合量将被确定。如果真的是u-PA 受体是u-PA依赖的蛋白水解酶的关键决定因素 入侵，了解其表达的调节可能会， 最终，导致新化合物的开发，从而降低 这些结合位点的展示，从而损害了 结肠肿瘤细胞的侵袭能力。在具体目标3中，角色 蛋白激酶C通路在u-PA受体调节中的作用 表达方式将会确定。在具体目标4中，该机制通过 哪些蛋白激酶C途径将刺激u-PA受体的表达 心意坚定。临床观察显示，20%的淋巴结- 阴性的患者会出现疾病复发。身份的鉴定 这一组中的患者将使辅助治疗合理化，这在 EH目前，仅限于淋巴结阳性患者。 相反，40%的淋巴结阳性患者可以通过手术治愈。 却要接受昂贵的、虚弱的化疗，因为没有足够的 识别这类患者的方法。在具体目标5中，我们 将确定u-PA受体水平是否是疾病的预测因子 结肠癌患者的复发。

High mortality rates in patients with colon cancer invariably reflect the spread of the disease to secondary organs. An understanding of the mechanisms which underscore this phase of the disease could ultimately, lead to therapeutic strategies aimed at combating tumor spread. The ability of tumor cells to degrade the surrounding extracellular matrix, via hydrolytic mechanisms, represents one of the first steps of metastasis. The plasminogen activator (PA), urokinase, (u-PA), has been implicated in tumor cell invasion via its ability to convert the inert plasminogen into the serine protease plasmin which cleaves key components of the extracellular matrix including laminin and type IV collagen. u-PA can be bound to a specific receptor on the cell, which does not down- regulated, thus concentrating the PA at the tumor cell surface. Receptor-bound u-PA activates plasminogen at a faster rate than fluid- phase u-PA. In specific Aim #1 the role of this binding site in vitro and in vivo invasion will be determined by gene transection studies and by making use of a soluble receptor which competes with cell surface receptors for u-PA binding. Several studies have shown that endogenous u-PA inhibitors can inhibit the fluid-phase plasminogen activator. However, the susceptibility of receptor-bound u-PA to these inhibitors is unclear at the present time. In Specific Aim #2 the role of endogenous u-PA inhibitor in blocking plasminogen activation by receptor- bound u-PA on colon cancer will be determined. If indeed the u-PA receptor is a critical determinant of u-PA-dependent proteolysis and invasion, an understanding of the regulation of its expression could, ultimately, lead to the development of novel compounds which decrease the display of these binding sites and which, consequently, impair the invasive capacity of colonic tumor cells. In Specific Aim #3, the role of Protein Kinase C pathways in the regulation of u-PA receptors expression will be determined. In Specific Aim #4, the mechanism by which Protein Kinase C pathways stimulate u-PA receptors expression will be determine. Clinical observations indicated the 20% of lymph node - negative patients will have disease recurrence. The identification of patients within this group would rationalize adjuvant therapy, which at eh present time, is restricted to lymph node-positive patients. Conversely, 40% of lymph node-positive patients are cured with surgery yet undergo costly debilitating chemotherapy since there is no adequate means of identifying this subject of patients. In Specific Aim #5, we will determine if u-PA receptor levels is a predictor of disease recurrence in colon cancer patients.