生物谷：美國波士頓和北卡羅萊納州的研究人員合作發(fā)現(xiàn)一種特殊的基因能夠抑制小鼠肺癌進程的關(guān)鍵步驟,。研究人員將這些發(fā)現(xiàn)公布在8月5日的《自然》雜志的網(wǎng)絡(luò)版上,。這種叫做LKB1的基因在小鼠中不但是非小細胞肺癌的一種腫瘤抑制基因,，而且其功能還可能比其他已知的抑制因子更加強大。
如果進一步的研究能夠證實LKB1在人類肺臟細胞中也有相同的效果，那么這種基因?qū)⒖赡苡绊懙椒切〖毎伟┑脑\斷和治療方式。如果攜帶LKB1突變的腫瘤生長的尤其迅速,，那么具有這種腫瘤的患者或許就可以采用更激烈點的療法來治療。
出生時就攜帶LKB1缺陷版本的人往往會發(fā)生Peutz-Jeghers綜合癥,，其主要特征是腸道生長和特定癌癥風險的增加,。這種基因的非遺傳性突變在一些肺癌中存在。這意味著LKB1正常情況下能夠抑制腫瘤的形成。突變版本的這種基因則不能起到癌癥“剎車”的功能,。（Peutz-Jeghers綜合癥又稱皮膚粘膜黑色素斑－胃腸多發(fā)性息肉綜合癥,，具有三大特征：多發(fā)性胃腸道息肉；特定部位的皮膚及粘膜的黑色素斑點,；遺傳性,。）
在實驗中，研究救人員對攜帶Kras基因的一種缺陷版本的小鼠進行了一系列實驗,，這種基因缺陷促進肺癌的形成和生長,。研究人員追蹤了攜帶LKB1突變的小鼠體內(nèi)的肺癌的發(fā)生，并且將其與兩種已經(jīng)研究較多的腫瘤抑制基因?qū)е碌漠惓Ｇ闆r進行比較,。
他們發(fā)現(xiàn)，當Kras與突變的腫瘤抑制基因合作時會導致肺癌的發(fā)生,，并且與突變的LKB1同時存在時更加強烈,。缺失LKB1的腫瘤生長的更快，并且比其他情況下更容易擴散,。研究表明,，LKB1在肺腫瘤的發(fā)展重要階段（起始、正常肺臟細胞向癌細胞的分化和轉(zhuǎn)移）起到重要作用,。另外,，對人類非小細胞肺組織的一項檢測表明，LKB1突變也起到一定作用,。
肺癌是一種常見的肺部惡性腫瘤,，其死亡率已占癌癥死亡率之首。絕大多數(shù)肺癌起源于支氣管粘膜上皮,，近年來,，隨著吸煙和各種環(huán)境因素的影響,世界各國特別是工業(yè)發(fā)達國家，肺癌的發(fā)病率和病死率均迅速上升,，死于癌病的男性病人中肺癌已居首位,。據(jù)上海市惡性腫瘤統(tǒng)計資料，在男性癌腫病例中,，肺癌發(fā)病率急劇增多,，居第一位。肺癌的分布情況右肺多于左肺,，下葉多于上葉,。起源于主支氣管、肺葉支氣管的肺癌稱為中央型肺癌,。起源于肺段支氣管遠側(cè)的肺癌,，位于肺的周圍部位者稱為周圍型肺癌。絕大多數(shù)肺癌起源于支氣管粘膜上皮，但亦有少數(shù)癌腫起源于肺泡上皮或支氣管腺體,。癌腫在成長過程中一方面治支氣管壁延伸擴展,，并穿越支氣管壁侵入鄰近肺組織形成腫塊，同時突入支氣管內(nèi)造成管腔狹窄或阻塞,。癌腫進一步發(fā)展播散則可從肺直接蔓延侵入胸壁,、縱隔、心臟,、大血管等鄰近器管組織,；經(jīng)淋巴道血道轉(zhuǎn)移到身體其他部位或經(jīng)呼吸道播散到其他肺葉。癌腫的生長速度和轉(zhuǎn)移擴散途徑取決于癌腫的組織學類型,、分化程度等生物學特性,。
肺癌共有四種不同類型：
1）小細胞肺癌：產(chǎn)生于肺的內(nèi)分泌細胞；
2）非小細胞肺癌：包括鱗癌,，產(chǎn)生于大氣道上皮細胞,；腺癌（包括大細胞癌），產(chǎn)生于肺的分泌區(qū),；支氣管肺泡癌,，產(chǎn)生于小氣囊上皮或肺泡上皮。
其中每一類型的癌都保持著所在肺區(qū)的細胞特性,，因此不同類型的癌其行為學特性亦不同,。為簡便計，我們將肺癌的四種類型分成兩大類：
1）小細胞肺癌,，產(chǎn)生于肺的內(nèi)分泌細胞,；
2）非小細胞肺癌，即所有其它類型,。正象我們將要闡述的,，對肺癌類型的正確判斷，尤其是對肺癌轉(zhuǎn)移部位的精確判斷,，是我們制定治療方案的關(guān)鍵,。著兩個關(guān)鍵因素還將決定所選治療方案的大致療效。
原始出處:
Nature advance online publication 5 August 2007 | doi:10.1038/nature06030; Received 15 March 2007; Accepted 19 June 2007; Published online 5 August 2007
LKB1 modulates lung cancer differentiation and metastasis
Hongbin Ji1,4,17, Matthew R. Ramsey10,12,17, D. Neil Hayes11, Cheng Fan10, Kate McNamara1,4, Piotr Kozlowski5, Chad Torrice11, Michael C. Wu3, Takeshi Shimamura1, Samanthi A. Perera1,4, Mei-Chih Liang1,4, Dongpo Cai1, George N. Naumov8, Lei Bao13, Cristina M. Contreras14, Danan Li1,4, Liang Chen1,4, Janakiraman Krishnamurthy10,11, Jussi Koivunen1, Lucian R. Chirieac6, Robert F. Padera6, Roderick T. Bronson9, Neal I. Lindeman6, David C. Christiani2, Xihong Lin3, Geoffrey I. Shapiro1,7, Pasi A. Jänne1,7, Bruce E. Johnson1,7, Matthew Meyerson1,15, David J. Kwiatkowski5, Diego H. Castrillon14, Nabeel Bardeesy16, Norman E. Sharpless10,11,12 & Kwok-Kin Wong1,7
Department of Medical Oncology, Dana-Farber Cancer Institute
Department of Environmental Health,
Department of Biostatistics, Harvard School of Public Health
Ludwig Center at Dana-Farber/Harvard Cancer Center,
Division of Translational Medicine,
Department of Pathology,
Department of Medicine, Brigham and Women's Hospital
Department of Surgery, Children's Hospital
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Genetics,
Department of Medicine,
Curriculum in Genetics and Molecular Biology, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
These authors contributed equally to this work.
Correspondence to: Nabeel Bardeesy16Norman E. Sharpless10,11,12Kwok-Kin Wong1,7 Correspondence and requests for materials should be addressed to K.-K.W. (Email: [email protected]) or N.E.S. (Email: [email protected]) or N.B. (Email: [email protected]).
Abstract
Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz–Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers1. Although uncommon in most sporadic cancers2, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines3, 4, 5. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.
