Cure rates for patients with squamous cell carcinomas (SCC) of the oral cavity have remained unchanged over the last decade this largely reflecting the inability of current clinical strategies to combat the local, regional and distant spread of the disease. The ability of tumor cells to spread to local and/or distant sites depends, at least in part, on the expression of one or more hydrolases which serve to degrade the basement membrane and surrounding extracellular matrix. The type IV collagenase MMP-9, which hydrolyzes basement membrane type IV collagen, has been implicated in tumor invasion in transformed rat embryo fibroblasts and osteosarcoma cells. However, its role in SCC invasion is unclear at the present time.
In Specific Aim #1, we will determine the role of MMP-9 in SCC invasion. If needed MMP-9 is a critical determinant of SCC invasion, a further understanding of the mechanism(s) by which MMP-9 is overexpressed in SCC could lead to novel anti-invasive agents which act by repressing the expression of the metalloproteinase. An analysis of the 5' flanking region of the MMP-9 gene indicated the presence of phorbol ester response elements (AP-1, AP-2, and NF-kB) suggesting that the expression of MMP-9 may be regulated by protein kinase C signal transduction pathways. With this in mind we will determine, in Specific Aim #2, the role of protein kinase C pathway (s) in the regulation of MMP-9 expression in cultured SCC.
In Specific Aim #3 we will determine the mechanism by which activated protein kinase C pathways leads to elevated levels of MMP-9 in cultured SCC of the oral cavity. The plasminogen activator, urokinase, has also been implicated in the process of tumor invasion via its ability to control the conversion of the inert plasminogen into the widely-acting serine protease plasmin. Plasmin hydrolyzes laminin and fibronectin which are integral constituents of the basement membrane and, in addition, has been reported to activate type IV collagenases.
In Specific Aim #4, we will determine the role of urokinase in SCC invasion. Since our preliminary data suggest a critical role of urokinase in the invasive character of at least a sub-population of SCC cell types we have taken the view that a further understanding of the mechanism(s) by which it is over-expressed in SCC of the oral cavity might lead to a new generation of agents whose anti-invasive actions depend on its ability to down-regulate the expression of UK.
In Specific Aim #5, we will determine whether gene amplification, increased mRNA stability or activation of the gene in trans is responsible for the over-expression of urokinase in cultured SCC.
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