Dependence of a human squamous carcinoma and associated paraneoplastic syndromes on the epidermal growth factor receptor pathway in nude mice.
Dependence of a human squamous carcinoma and associated paraneoplastic syndromes on the epidermal growth factor receptor pathway in nude mice.
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发表时间：
1991-05
期刊：
影响因子：
11.2
通讯作者：
Toshiyuki Yoneda;M. Alsina;Kazuya Watatani;Francoise Bellot;Joseph Schlessinger;G. R. Mundy
中科院分区：
文献类型：
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作者：
Toshiyuki Yoneda;M. Alsina;Kazuya Watatani;Francoise Bellot;Joseph Schlessinger;G. R. Mundy
表皮生长因子受体（EGFR）水平的增加已被证明在鳞状细胞癌。最近，我们报道了一个口腔鳞状细胞癌（MH-85），它伴有几种副肿瘤综合征，包括高钙血症和恶病质。该肿瘤在裸鼠（BALB/c，nu/nu，雄性，4-6周龄）中诱导相同的副肿瘤综合征。Scatchard分析显示MH-85中存在两类EGFR。高亲和力受体的解离常数和结合位点数分别为38 pM和5 x 10（4）/细胞，低亲和力受体的解离常数和结合位点数分别为2.2 nM和6 x 10（5）/细胞。MH-85在培养物中的生长被表皮生长因子（EGF）刺激，并被针对人EGFR的单克隆抗体108抑制，所述单克隆抗体108识别EGF受体的细胞外结构域。手术切除雄性裸鼠的下颌下腺导致血浆EGF水平急剧下降，肿瘤生长、高钙血症和恶病质显著减少。当EGF（5微克/小鼠，每2天持续6周，i. p.）给予这些切除涎腺的动物，肿瘤生长增加，高钙血症平行增加。当单克隆抗体108（lmg/小鼠，i. p.）在MH-85肿瘤植入后1、5和10天给予，肿瘤形成延迟，这导致高钙血症和恶病质的延迟发作。此外，当在表现出大肿瘤和严重高钙血症和恶病质的裸鼠中注射抗体6次时，肿瘤生长显著减少，这伴随着高钙血症和恶病质的逆转。这些结果表明，人鳞状细胞癌MH-85的生长依赖于EGFR途径，并且随后的高钙血症和恶病质的发展依赖于肿瘤生长。他们还表明，干扰EGFR途径的药物可能在某些人类肿瘤中具有作为抗癌药物的治疗潜力。
Increased levels of epidermal growth factor receptor (EGFR) have been shown on squamous cell carcinomas. Recently, we described a squamous cell carcinoma (MH-85) derived from the oral cavity which was associated with several paraneoplastic syndromes including hypercalcemia and cachexia. This tumor induced the same paraneoplastic syndromes in nude mice (BALB/c, nu/nu, male, 4-6 weeks old). Scatchard analysis revealed that there are two classes of EGFR in MH-85. The dissociation constant and number of binding sites for the high affinity receptors were 38 pM and 5 x 10(4)/cell, respectively, and 2.2 nM and 6 x 10(5) cell, respectively, for the low affinity receptors. Growth of MH-85 in culture was stimulated by epidermal growth factor (EGF) and inhibited by monoclonal antibody 108 to human EGFR, which recognizes the extracellular domain of the EGF receptor. Surgical removal of submandibular glands from male nude mice resulted in a dramatic decrease in plasma EGF levels and a significant reduction of tumor growth, hypercalcemia, and cachexia. When EGF (5 micrograms/mouse, every 2 days for 6 weeks, i.p.) was administered to these sialoadenectomized animals, tumor growth increased, with a parallel increase in hypercalcemia. When monoclonal antibody 108 (1 mg/mouse, i.p.) was given 1, 5, and 10 days after MH-85 tumor implantation, tumor formation was retarded, which resulted in delayed onset of hypercalcemia and cachexia. Moreover, when the antibody was injected 6 times in nude mice exhibiting large tumors and profound hypercalcemia and cachexia, there was a striking decrease in tumor growth, which was accompanied with a reversal of hypercalcemia and cachexia. These results indicate that growth of the human squamous cell carcinoma MH-85 is dependent on the EGFR pathway and that subsequent development of hypercalcemia and cachexia is dependent on tumor growth. They also suggest that agents which interfere with the EGFR pathway may have therapeutic potential as anticancer agents in some human tumors.