Alterations in integrin expression, distribution and regulation during carcinogenesis.
AuthorWitkowski, Colette Mae.
Committee ChairCress, Anne E.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractMetastatic cancer is the most difficult aspect in the treatment of cancer. Cancer cells that have metastasized show altered adhesion compared to normal cells of the same origin. Altered cell adhesion of cancer cells is central to the process of invasion and metastasis. A family of cell adhesion molecules termed integrins have been shown to be the cell adhesion molecules that are altered on cancer cells. These alterations and the mechanisms responsible for altering integrin expression, function and distribution during tumor progression currently are not fully understood. Altered integrin expression was found to affect the tumorigenicity of human prostate carcinoma cells. The integrin profiles on four human prostate cell lines were analyzed using fluorescence activated cell sorting and immunoprecipitation of surface labeled proteins. The tumorigenicity was tested by injection into SCID mice. Different integrin profiles affected tumor formation differently. Increased expression of α5β1 and α6β4 decreased invasion. Altered non-functioning receptors also contributed to the lack of tumorigenicity. These data show that alterations in integrin expression affect the tumorigenic potential of human prostate cells. A mouse model of skin carcinogenesis comprising normal, benign and malignant stages from a common lineage, was analyzed to determine at which stage integrin expression was altered. The malignant carcinoma stage demonstrated a decrease in the surface expression of integrin α6β4 and loss of the normal basal lateral distribution of this integrin. The changes in the α6β4 on the malignant carcinoma cells parallels integrin expression results in situ. This in vitro cell model system provided an opportunity to study the mechanisms of aberrant integrin expression. The results show the β4 subunit expression in this model is altered by down regulation of the mRNA and posttranslational cleavage resulting ultimately in decreased surface expression. The β4 in the malignant cells appears to be susceptible to degradation due to loss of protein-protein interactions involving the 100 kD β4 cytoplasmic domain. These protein interactions localize the α6β4 to the basal surface. Loss of these interactions results in non-polar distribution and potential susceptibility of the α6β4 to proteolytic degradation. These mechanisms contribute to altered surface expression on cancer cells.