Regulation of urokinase receptor expression in colon cancer

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Linked publications & trials

Abstract

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.