Squamous cell carcinoma of the oral cavity spreads by local extension and by lymphatic metastasis. The processes by which carcinoma cells at the primary site invade through the basement membrane, enter the lymphatics, and then arrest and grow in lymph nodes are poorly understood. Motility factors, such as scatter factor (SF), are believed to be important in facilitating tumor invasion. Stromal/mesenchymal cells neighboring the oral mucosa secrete SF, which appears to induce a set of divergent responses in squamous cell carcinoma cells. These types of responses may include (i) growth stimulation or inhibition, (2) morphogenesis and formation of organoid structures, and (3) motogenic activity that induces cell-cell dissociation, locomotion, and invasion. The cellular receptor for SF is the Met protein, the product of the C-met proto-oncogene. Preliminary studies using cultured cell lines indicate that the migratory or invasive phenotype in response to SF is directly related to the level of c-met receptor expression. Another cellular attribute that influences invasion is the presence of functional E-cadherin receptor, which is involved in cell-cell adhesion and adherens junction formation. Moderately differentiated squamous cell carcinoma cells usually have high levels of E-cadherin receptor, whereas poorly differentiated tumor cells have low levels of the receptor. We propose to test the following hypothesis: The type of biological response -- mitogenic, morphogenic, or migratory -- produced in squamous cell carcinoma cells by SF is dependent on their level of c-met receptor expression, presence of functional E-cadherin, and degree of cell differentiation. We will address the following questions: (1) Are there differences in the levels of c-met receptor expression or activity between the SF-responsive and nonresponsive squamous cell carcinoma cell lines? (2) What types of biological responses, mitogenic, morphogenic, or motogenic, are induced in squamous cell carcinoma cell lines by SF? (3) Will overexpression of c-met receptor by cDNA transfection in squamous cell carcinoma cells alter their response to SF and their in vivo phenotype? (4) How does E-cadherin modulate the SF- induced response in squamous cell carcinoma cells? These proposed studies will provide relevant information about the mechanisms responsible for the diversity of the cellular responses induced by SF and should help define the role of the c-met receptor in the pathogenesis and progression of squamous cell carcinoma. In addition, this knowledge may lead to development of novel prognostic indicators and therapeutic techniques that will facilitate early detection and suggest treatment strategies for the disease.
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