Squamous cell carcinoma of the head and neck (SCCHN) is a frequently fatal disease with few available therapeutic modalities. Information concerning the growth factors involved in the development and maintenance of SCCHN may improve treatment options; such an understanding has resulted in new approaches to therapy in some cancers such as anti-EGF receptor antibodies to treat squamous cell carcinoma of the lung. The possibilities for this type of therapy for SCCHN is unknown since the role of growth factors has yet to be examined in a systematic fashion. The epithelial growth factor, transforming growth factor alpha (TGF- alpha), which shares the same cell surface receptor, the epidermal growth factor receptor (EGFR), with epidermal growth factor (EGF), is a likely candidate in this regard. In our initial studies we have detected elevated levels of EGFR and TGF-alpha mRNA in fresh tissue samples of tumor and histologically normal mucosa excised from patients with SCCHN compared with levels in normal mucosa resected from patients without cancer. The overall goals of this project are: (1) to determine the molecular mechanism of this apparent upregulation of EGFR and TGF-alpha mRNA using SCCHN cell lines (DNA versus RNA transcription versus RNA message stability), (2) to confirm elevation of TGF-alpha and EGFR at the protein level in fresh tissues and SCCHN cell lines, (3) to demonstrate the existence of an autocrine regulatory pathway involving EGFR and its ligand, TGF-alpha, in selected SCCHN cell lines using proliferation assays with human recombinant TGF-alpha and monoclonal antibodies to receptor and ligand, (4) to attempt to interrupt this pathway in SCCHN cell lines with differentiation agents such as retinoic acid (RA); if RA inhibits proliferation, we will examine if RA acts through down- regulation of EGFR or TGF-alpha mRNA synthesis using Northern blot analysis, (5) to examine the production of EGFR and TGF-alpha mRNA in premalignant lesions such as oral leukoplakia and erythroplasia, (6) to document the cellular population(s) responsible for this increased production of EGFR and TGF-alpha mRNA in fresh tissue specimens using in situ RNA hybridization techniques. The demonstration of an autocrine growth pathway involving EGFR and its ligand, TGF-alpha, in SCCHN would be a major advance in our understanding of the pathogenesis of this cancer and would provide opportunities for new preventative and therapeutic strategies based on modulation of this pathway.
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