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

表皮生长因子受体在致瘤颌下腺上皮细胞体内外增殖中的作用研究

基本信息

批准号：
07457488
负责人：
SAKUDA Masayoshi
金额：
$ 3.71万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

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.

我们将人表皮生长因子受体基因转染到小鼠下颌下腺上皮细胞中，并与未转染的TMSG细胞比较，检测转染后细胞增殖能力的变化。转染细胞（TMSG-EGFR）表面hEGFR分子过表达。TGF-α和EGF对TMSG-EGFR细胞增殖有明显的促进作用，且呈剂量依赖性。TMSG-EGFR细胞表现出对强烈抑制TMSG细胞增殖的TGF-β的抗性。TMSG-EGFR细胞在协同小鼠中形成的肿瘤明显比TMSG细胞更快、更大。由于培养的TMSG-EGFR细胞对EGF高度敏感，因此我们在体内研究了EGFR对TMSG-EGFR肿瘤生长的影响。为了研究这一点，雄性小鼠的颌下腺被切除，已知其产生超过95%的EGF。唾液腺切除小鼠的血浆EGF水平在手术后3至5周显著降低。TMSG-EGFR肿瘤在切除涎腺的小鼠中表现出明显的生长迟缓，而TMSG肿瘤的生长没有表现出变化。这些结果表明TMSG-EGFR肿瘤生长受下颌下腺分泌的循环EGF的影响，培养物和小鼠中的TMSG-EGFR肿瘤生长被酪氨酸激酶抑制剂显著减少，而TMSG生长不受该试剂的影响。另外，（1）EGFR在癌细胞中的过表达不仅增加对EGF的应答性，而且可能导致获得对其它生长因子的应答性和对生长抑制因子的抗性。这些变化，至少部分地，可能是EGFR表达异常的癌细胞的总体增殖能力增加的原因。(2)酪氨酸激酶的药理学抑制剂可能是有效的抗癌剂。