Regulation of urokinase receptor expression in colon cancer

大量研究表明，细胞表面尿激酶受体(u-PAR)参与调节肿瘤的生长和发展。较高的u-PAR水平促进生长，而较低的u-PAR促进肿瘤休眠，后者保护肿瘤免受微环境压力，如缺氧、营养缺乏等。U-PAR还与丝氨酸蛋白水解酶尿激酶结合，从而增加纤溶酶的形成和细胞外基质蛋白的周转，从而促进肿瘤细胞的迁移/侵袭。矛盾的是，u-PAR依赖的蛋白分解作用的减弱有利于血栓包裹的肿瘤细胞，因为它保持了纤维蛋白的完整性，将肿瘤细胞与淋巴因子激活的杀伤细胞隔离开来。我们已经做了一个有趣的观察，在一些结肠癌细胞中，克隆群体在高和低细胞表面密度之间振荡，与后者分离的致瘤性降低。有趣的是，改变后的u-PAR细胞表面显示本质上是翻译后的。在特定的目标#1中，我们将确定u-PAR显示可塑性在结肠癌中的流行率，如果肿瘤发生/休眠状态的改变反映了细胞表面u-PAR密度的这种波动，以及向下转移到低u-PAR的亚群在保护LAK细胞的杀伤活性方面是否具有优势。在特定的目标#2中，我们将确定u-PAR缺陷人群中u-PAR的糖基化改变是否是未成熟蛋白溶酶体降解的初始刺激因素。

A strong body of work has implicated the cell surface urokinase receptor (u-PAR) in modulating tumor growth and progression. Elevated u-PAR levels yield increased growth while low u-PAR promotes tumor dormancy the latter protective against microenvironmental stress such as hypoxia, nutrient deprivation. The u- PAR also binds the serine protease urokinase thus increasing plasmin formation and extracellular matrix protein turnover to promote tumor cell migration/invasion. Paradoxically, diminished u-PAR-dependent proteolysis benefits thrombus-enveloped tumor cells by virtue of maintaining the integrity of the fibrin “cloaking” the tumor cells from lymphokine-activated killer cells. We have made the intriguing observation that in some colon cancer cells, clonal populations oscillate in u-PAR display between high and low cell surface density with reduced tumorigenecity segregating with the latter. Interestingly, the altered u-PAR cell surface display is posttranslational in nature. In Specific Aim #1 we will determine the prevalence of u-PAR display plasticity in colon cancer, if altered tumorigenecity/dormancy mirrors this oscillation in cell surface u-PAR density and whether the sub-population down-shifted to low u-PAR has an advantage with respect to protection from the killing activity of LAK cells. In Specific Aim # 2, we will determine whether altered glycosylation of u-PAR in the u-PARdeficient population is an initial stimulus for lysosomal degradation of the immature protein.