Studies on the role of epidermal growth factor receptors in the proliferation of tumorigenic submandibular gland epithelial cells in vitro and in vivo

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We transfected human epidermal growth factor receptor gene into tumorigenic mouse submandibular glamd epitelial cells, and examined their changes in a proliferative capacity after the transfection in comparison with untransfected TMSG cells. Transfected cells (TMSG-EGFR) showed overexpressed hEGFR molecule on their surface. TMSG-EGFR cell proliferation was much faster than that of TMSG cekks and etimulated by EGF and TGF-alpha in dose dependent manner. TMSG-EGFR cells demonstrated a resistance to TGF-beta which strongly inhibited TMSG cell proliferation. TMSG-EGFR cells formed markedly faster and larger tumors in synergic mice than did TMSG cells. Since TMSG-EGFR cells in culture were highly resposive to EGF.Effects of EGFR on TMSG-EGFR tumor growth in vivo was examined. To study this, submandibular glands, which are known to produce more than 95% of EGF in male mice were removed. Plasma EGF levels in sialoadenectomized mice were markedly decreased for 3 to 5 weeks after surgery. TMSG-EGFR tomors shwed prfoundly retarded growth in the sialoadenectomized mice, whereas TMSG tumor growth showed no change. These results suggest that TMSG-EGFR tumor growth was influenced by circulating EGF which was secreted form submandibular glands, TMSG-EGFR tumor growth in culture and in mice was significantly diminished by a tyrosine kinase inhibitor, whereas TMSG growth was not affected by this agent. In xonxlusion, (1) overexpression of EGFR in cancer cells not only increase a responsiveness to EGF but might cause an acquisition of a responsiveness to other growth factors and a resistance to growth inhibitory factors. These changes, at least in part, might account for an increased overall proliferative capacity of cancer cells with aberrant EGFR expression. (2) there might be a possibility that pharmacologic inhibitor of tyrosine kinases are potent anti-cancer agents.