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.
The urokinase receptor (u-PAR) contributes to tumor growth, dormancy and metastatic spread in several tumor types including colon cancer. The thrust of the current application is to understand the mechanisms that regulate the amount of this protein displayed at the tumor cell surface. This information could ultimately be of utility in managing tumor growth and the dissemination of cancer from the primary site.
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