PREFERENTIAL ACTIVATION OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR IN HUMAN COLON-CARCINOMA LIVER METASTASES IN NUDE-MICE

Increased epidermal growth factor receptor (EGF-R) gene expression and functional protein levels correlate with the metastatic potential of human colon carcinoma (HCC) cells in nude mice. The purpose of this st udy was to determine whether the production of liver metastases by HCC cells depends on the EGF-R activation status and whether different or gan microenvironments influence this activation. Using two independent monoclonal antibodies specific for the activated (i.e., tyrosine-phos phorylated) EGF-R, increased immunoreactivity was observed in HCC cell s growing as metastatic lesions in the livers of athymic nude mice. St aining was observed throughout: these lesions, both peripherally and c entrally. In contrast, little or no immunoreactivity for activated EGF -R was observed in primary tumors growing orthotopically in the cecum or ectopically in the subcutis of nude mice. Immunohistochemistry for total EGF-R levels (irrelevant of activation status) demonstrated simi lar levels of immunoreactivity in HCC tumors growing in the cecum, sub cutis, or liver of nude mice, indicating that total ECF-R levels are n ot altered after growth in these different microenvironments. Controls included immunohistochemistry for total and activated EGF-R levels in HCC cells growing in vitro under serum-free or EGF-stimulated conditi ons and A431-epidermoid carcinoma growing in nude mice. Western blot a nalyses confirmed the specificity of the antibodies for the activated EGF-R. These results suggest that the production of liver metastasis b y HCC cells depends in part on the response of tumor cells to organ-de rived growth factors and hence the activation of specific cell surface tyrosine kinase receptors.