5月16日,纽约Memorial Sloan Kettering 癌症中心的Katerina Politi 、Harold Varmus博士和他们的同事在《基因与发育》杂志报道,他们开发了一个肺腺癌的动物模型,可以对测试人类肺癌的治疗效果有巨大的作用。
Politi 博士解释说:“我们希望使用这些模型去理解表皮生长因子受体基因的变异导致肺部肿瘤的途径。除此以外,这个模型还可以允许我们去评价新药和联合药物的疗效,从而去研究抗酪氨酸激酶受体抑制子的分子机制。”那些表皮生长因子受体变异的肺癌病人一般会对抑制表皮生长因子受体的药物(例如易瑞沙和埃罗替尼)有着较好的反应。
Politi博士和他的同事们在老鼠体内改造了一种表皮生长因子受体,它可以在肺细胞内任意开关。这些诱导的表皮生长因子受体变异的老鼠可以使得研究人员评价表皮生长因子受体变异对肺癌的形成、恶化所起的作用,以及对化疗的反应。
研究人员发现表皮生长因子受体的变异可以使得肺部肿瘤发生。既可以关闭变异的表皮生长因子受体基因,也可以通过药物有效的抑制肿瘤的形成。
Published online before print May 16, 2006
Lung adenocarcinomas induced in mice by mutant EGF receptors foundin human lung cancers respondto a tyrosine kinase inhibitor orto down-regulation of the receptors
Katerina Politi1,4, Maureen F. Zakowski2, Pang-Dian Fan1, Emily A. Schonfeld1, William Pao3 and Harold E. Varmus1
1 Program in Cancer Biology and Genetics, 2 Department of Pathology, and the 3 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Nearly 90% of the EGFR mutations are either short, in-frame deletions in exon 19 or point mutations that result in substitution of arginine for leucine at amino acid 858 (L858R). To study further the role of these mutations in the initiation and maintenance of lung cancer, we have developed transgenic mice that express an exon 19 deletion mutant (EGFRL747–S752) or the L858R mutant (EGFRL858R) in type II pneumocytes under the control of doxycycline. Expression of either EGFR mutant leads to the development of lung adenocarcinomas. Two weeks after induction with doxycycline, mice that express the EGFRL858R allele show diffuse lung cancer highly reminiscent of human bronchioloalveolar carcinoma and later develop interspersed multifocal adenocarcinomas. In contrast, mice expressing EGFRL747–S752 develop multifocal tumors embedded in normal lung parenchyma with a longer latency. With mice carrying either EGFR allele, withdrawal of doxycycline (to reduce expression of the transgene) or treatment with erlotinib (to inhibit kinase activity) causes rapid tumor regression, as assessed by magnetic resonance imaging and histopathology, demonstrating that mutant EGFR is required for tumor maintenance. These models may be useful for developing improved therapies for patients with lung cancers bearing EGFR mutations.
[Keywords: EGFR; lung adenocarcinoma; mice; tyrosine kinase inhibitor]
Received February 6, 2006; revised version accepted March 24, 2006.
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4 Corresponding author.
E-MAIL politik@mskcc.org ; FAX (212) 717-3125.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1417406
Supplemental material is available at http://www.genesdev.org
肺癌
一、解剖学分类:
1、中央型肺癌
生长在叶、段以上的支气管,位于肺门附近者的占3/4,以鳞癌和小细胞未分化癌多见。
2、周围型肺癌
生长在段以下的支气管,位于的边缘的占1/4,以腺癌和大细胞癌最为常见。
二、按组织学分类
1、 鳞癌
为最常见类型,约占原发性肺癌40-50%,肿瘤多生长在接近肺门的叶、段支气管,并有向管腔内生长的倾向,常早期引起支气管狭窄,导致肺不张,或阻塞性肺炎。鳞癌生长缓慢,转移晚,手术机会多,但放疗和化疗治疗不如小细胞未分化癌敏感。
2、 小细胞分化癌
是肺癌中恶性程度最高的一种,约占原发性肺癌的1/5。多发于肺门附近的大支气管,倾向于粘膜下层生长。癌细胞生长快侵袭力强,远处转移早,常转移至脑、肝、骨、肾上腺等脏器。本型对放疗和化疗特别敏感。
3、 腺癌
多生长在肺边缘小支气管粘液腺,因此周围型肺癌中以腺癌为最常见。腺癌倾向于管外生长,也可向肺泡壁蔓延。腺癌富血管,故局部浸润和血行转移较鳞癌早,易转移。
4 、 大细胞癌:
是一种由大核、核仁明显、胞浆丰富的大细胞构成的肿瘤。不具有鳞癌、腺癌或小细胞癌的任何形态学特征。光镜下癌细胞大,未见有任何特异性分化特征时,可以诊断为大细胞癌。
5、周围型腺鳞癌、中心型鳞腺癌(此类型少见)
6、未分化癌(此类型少见)
7、类癌(此类型少见)
左肺上叶中央型肺癌。支气管体层(上图)示左肺上叶支气管完全闭塞,阻塞端呈杯口状(黑箭头)。支气管造影(下图)示碘油不能进入阻塞的左上叶支气管(箭头)。