EGF-R Modulation and Responses in Colon Carcinoma - The research proposed in this application will examine the role of epidermal growth factor receptor (EGF-R) and transforming growth factor-alpha (TGF-a) levels of expression upon the growth characteristics of individual human colon tumor cell lines that have been grouped into three classes that are based upon their biological characteristics. These three cell line classes draw upon a bank of more than 20 human colon tumor cell lines that have been adapted to growth in chemically defined, serum-free medium and have been characterized in terms of their extent of differentiation, tumorigenicity, growth in soft agarose and production of mucins. The relationship of EGF-R expression and TGF-a production to cell growth will be studied by determining the levels of receptor and factor expression in colon tumor cell lines that diverge widely in their growth rate and extent of differentiation, by varying the level of exogenous TGF-a and/or epidermal growth factor (EGF), as well as by modulating the levels of functional EGF receptor in at least two cell lines from each of the two most phenotypically divergent of the 3 classes of human colon tumor cell lines. This study will focus upon the following questions: (i) do the faster growing colon tumor cell lines express more functional TGF-a, (ii) is the level of cell-surface EGF-R directly related to level of EGF-R mRNA expression, (iii) do TGF-a and EGF differ in their capacity to activate EGF-R tyrosine specific protein kinase activity, (iv) do TGF-a and EGF differ with regard to their capacity to produce different sites of amino acid phosphorylation of the EGF-R, and (v) how does altered EGF-R number and function influence colon cell growth and differentiation? By this approach a better understanding of the relationship between natural levels of TGF-a/EGF-R expression and colon tumor cell growth characteristics will be achieved. Furthermore, the influence of EGF-R number on the basal cell growth, cell growth requirements, and extent of differentiation for individual colon cell line classes will be determined.
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