ROLE OF THE UROKINASE RECEPTOR IN INVASIVE COLON CANCER

结肠癌患者的高死亡率无一例外地反映了

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.