5月16日，紐約Memorial Sloan Kettering 癌癥中心的Katerina Politi ,、Harold Varmus博士和他們的同事在《基因與發(fā)育》雜志報道,，他們開發(fā)了一個肺腺癌的動物模型,，可以對測試人類肺癌的治療效果有巨大的作用。
Politi 博士解釋說：“我們希望使用這些模型去理解表皮生長因子受體基因的變異導致肺部腫瘤的途徑,。除此以外,，這個模型還可以允許我們?nèi)ピu價新藥和聯(lián)合藥物的療效，從而去研究抗酪氨酸激酶受體抑制子的分子機制,。”那些表皮生長因子受體變異的肺癌病人一般會對抑制表皮生長因子受體的藥物(例如易瑞沙和埃羅替尼)有著較好的反應,。
Politi博士和他的同事們在老鼠體內(nèi)改造了一種表皮生長因子受體，它可以在肺細胞內(nèi)任意開關,。這些誘導的表皮生長因子受體變異的老鼠可以使得研究人員評價表皮生長因子受體變異對肺癌的形成,、惡化所起的作用,，以及對化療的反應。
研究人員發(fā)現(xiàn)表皮生長因子受體的變異可以使得肺部腫瘤發(fā)生,。既可以關閉變異的表皮生長因子受體基因,，也可以通過藥物有效的抑制腫瘤的形成。
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 [email protected] ; 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,、解剖學分類：
1,、中央型肺癌
生長在葉、段以上的支氣管,，位于肺門附近者的占３／４,，以鱗癌和小細胞未分化癌多見。
2,、周圍型肺癌
生長在段以下的支氣管,，位于的邊緣的占１／４，以腺癌和大細胞癌最為常見,。
二,、按組織學分類
1、 鱗癌
為最常見類型,，約占原發(fā)性肺癌４０－５０％,，腫瘤多生長在接近肺門的葉、段支氣管,，并有向管腔內(nèi)生長的傾向,，常早期引起支氣管狹窄，導致肺不張,，或阻塞性肺炎,。鱗癌生長緩慢，轉移晚,，手術機會多,，但放療和化療治療不如小細胞未分化癌敏感。
2,、 小細胞分化癌
是肺癌中惡性程度最高的一種,，約占原發(fā)性肺癌的１／５。多發(fā)于肺門附近的大支氣管,，傾向于粘膜下層生長,。癌細胞生長快侵襲力強，遠處轉移早,，常轉移至腦,、肝、骨,、腎上腺等臟器,。本型對放療和化療特別敏感,。
3、 腺癌
多生長在肺邊緣小支氣管粘液腺,，因此周圍型肺癌中以腺癌為最常見。腺癌傾向于管外生長,，也可向肺泡壁蔓延,。腺癌富血管，故局部浸潤和血行轉移較鱗癌早,，易轉移,。
4 、 大細胞癌：
是一種由大核,、核仁明顯,、胞漿豐富的大細胞構成的腫瘤。不具有鱗癌,、腺癌或小細胞癌的任何形態(tài)學特征,。光鏡下癌細胞大，未見有任何特異性分化特征時,，可以診斷為大細胞癌,。
5、周圍型腺鱗癌,、中心型鱗腺癌（此類型少見）
6,、未分化癌（此類型少見）
7、類癌（此類型少見）
左肺上葉中央型肺癌,。支氣管體層（上圖）示左肺上葉支氣管完全閉塞,，阻塞端呈杯口狀（黑箭頭）。支氣管造影（下圖）示碘油不能進入阻塞的左上葉支氣管（箭頭）,。
