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.

Public Health Relevance

The urokinase receptor (u-PAR) contributes to tumor growth, dormancy and metastatic spread. The thrust of the current application is to understand the mechanisms that regulate the amount of this protein dis- played at the tumor cell surface.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA058311-15
Application #
7866600
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
1994-07-01
Project End
2011-12-30
Budget Start
2010-07-01
Budget End
2011-12-30
Support Year
15
Fiscal Year
2010
Total Cost
$263,200
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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