The submandibular salivary gland (SSG) synthesizes and secretes growth factors, homeostatic factors and digestive enzymes. This versatility in functional activity provides an important model system to study the regulation of normal cell processes and abnormal disease states. This project will continue to explore and define the response of SSG epithelial cells to signals generated by activated oncogenes with different functions. The interactions between activated oncogenes and defined types of epithelial cells, the most common targets for human cancer, are largely unexplored. Our previously funded studies with SSG cells in culture (1) established modulatory effects of hormones and the extracellular matrix on the synthesis of the SSG product, epidermal growth factor (EGF) and (2) defined SSG epithelial cell phenotypes with a panel of rat monoclonal antibodies. Most important, two functionally distinct activate oncogenes, v-src and v-myc, were shown to affect both the growth behavior of SSG epithelial cells and deregulate hormone-dependent EGF synthesis. Immunological characterization of seven SSG oncogene-immortalized cell lines suggested that the effects of v-src are restricted to the EGF- synthesizing cells of the granular convoluted tubules (GCT). Secretion of mitogenic activity by one of the GCT-like cell lines with potential autocrine and/or paracrine effects was established. The proposed 5-year program will expand on this knowledge and will initiate related studies with a Ha-ras transgenic mouse model which exhibits a high incidence of salivary gland tumors. The EFG-specific products of the GCT-like cell lines will be further characterized to establish precursor-product relationships, to confirm identity with EGF and to analyze EGF precursor mRNA. The relationship of the mitogenic activity to EGF will be established by molecular sieve chromatography, reactivity with EGF-specific antibodies and ability to both compete for binding to the EGF receptor and stimulate anchorage independent growth. Potential autocrine and/or paracrine growth effects will be explored and then, related to the status of the EGF receptor. Antibody blocking experiments will be performed to determine whether mitogenic stimulation is indeed mediated through an extracellular mechanism. Rigorous proof of the restricted immortalizing effects of v-src in the SSG will be established with SSGs devoid of GCTs. Finally, availability of a transgenic mouse model to further examine issues of oncogene effects on SSG behavior presents an approach to determine the physiological relevance of our observations. These studies will provide insights into the long term goal of this research, namely, to elucidate the mechanism(s) of oncogene-induced SSG epithelial cell alterations in particular, with respect to the potential mediatory role of EGF and its receptor.
| Ogbureke, K U; MacDaniel, R K; Jacob, R S et al. (1995) Distribution of immunoreactive transforming growth factor-alpha in non-neoplastic human salivary glands. Histol Histopathol 10:691-6 |
| Durban, E M; Nagpala, P G; Barreto, P D et al. (1995) Emergence of salivary gland cell lineage diversity suggests a role for androgen-independent epidermal growth factor receptor signaling. J Cell Sci 108 ( Pt 6):2205-12 |
| Durban, E M (1990) Mouse submandibular salivary epithelial cell growth and differentiation in long-term culture: influence of the extracellular matrix. In Vitro Cell Dev Biol 26:33-43 |
