Invasion and metastasis are usually the most dangerous properties of cancers, and in oral SCC recurrence of locoregional disease that is difficult to control accounts for most morbidity and mortality. The invasiveness of oral cancers frequently requires surgical resections that impair important physiological functions, including speech and swallowing. The therapy of oral cancer may be approaching a plateau due to the efficacy and toxicity of the agents used for post-surgical treatment; therefore, addressing the mechanisms of invasion of oral cancers may ultimately lead to the development of novel treatments that attenuate the locoregional spread of these cancers and consequently increase the quality of life and survival times of oral cancer patients. To invade and metastasize cancer cells must penetrate basement membranes, and we have developed methods to assess the risk of squamous cell invasion at early stages of carcinoma development. Using specific anti-peptide monoclonal (MAb) and polyclonal (PAb) antibody reagents we have examined the amounts and distribution of three important basement membrane- degradative enzymes in a series of early (stage I/II) oral cancers at two different locations. Our preliminary results indicate that patients with disease recurrence show histochemical overexpression of these three enzymes in their early stage tumors, consistent with the role of these enzymes in basement membrane invasion. Our hypothesis is that overexpression of degradative enzymes is reflective of the transition from a carcinoma in situ state to an invasive state and that this will be related to recurrence of oral cancer. In the proposed project we will use the anti-peptide PAb and MAb reagents for immunoassays and immunohistochemical studies. We will determine in retrospective and prospective studies if heparinase, urokinase and two metalloproteinases (MMPs), either individually or as a combination, is predictive of tumor recurrence in patients with stage I/II SCCs of the floor of mouth and tongue. Differences between tumors at the same or different primary sites and their ability to recur will be examined to determine if these assays are of prognostic and monitoring value. The results could lead to the development of new approaches for the prognosis and monitoring of oral cancer recurrence.
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