生物谷： 来自美国波士顿和北卡罗莱纳州的研究人员合作发现一种特殊的基因能够抑制小鼠肺癌进程的关键步骤。研究人员将这些发现公布在8月5日的《自然》杂志的网络版上。这种叫做LKB1的基因在小鼠中不但是非小细胞肺癌的一种肿瘤抑制基因，而且其功能还可能比其他已知的抑制因子更加强大。
肺癌是一种常见的肺部恶性肿瘤，其死亡率已占癌症死亡率之首。绝大多数肺癌起源于支气管粘膜上皮，近年来，随着吸烟和各种环境因素的影响,世界各国特别是工业发达国家，肺癌的发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。据上海市恶性肿瘤统计资料，在男性癌肿病例中，肺癌发病率急剧增多，居第一位。肺癌的分布情况右肺多于左肺，下叶多于上叶。起源于主支气管、肺叶支气管的肺癌称为中央型肺癌。起源于肺段支气管远侧的肺癌，位于肺的周围部位者称为周围型肺癌。绝大多数肺癌起源于支气管粘膜上皮，但亦有少数癌肿起源于肺泡上皮或支气管腺体。癌肿在成长过程中一方面治支气管壁延伸扩展，并穿越支气管壁侵入邻近肺组织形成肿块，同时突入支气管内造成管腔狭窄或阻塞。癌肿进一步发展播散则可从肺直接蔓延侵入胸壁、纵隔、心脏、大血管等邻近器管组织；经淋巴道血道转移到身体其他部位或经呼吸道播散到其他肺叶。癌肿的生长速度和转移扩散途径取决于癌肿的组织学类型、分化程度等生物学特性。
Lkb1肿瘤抑制基因所发生的突变见于Peutz–Jeghers综合症患者，这些患者癌症发病率增加。现在，Lkb1突变已在非小细胞肺癌的鳞状肿瘤亚型中被发现。在一个Lkb1缺失与K-Ras突变相结合的肺癌小鼠模型中，出现了比只有K-Ras突变时更有侵略性的肿瘤，这些肿瘤经常被划分为鳞状大细胞肿瘤。所以，Lkb1缺失调控肺癌分化，而Lkb1缺失还可能是预测疾病发展和扩散的一个有用的标记。由LKB1调控的通道代表可能的治疗目标。
如果进一步的研究能够证实LKB1在人类肺脏细胞中也有相同的效果，那么这种基因将可能影响到非小细胞肺癌的诊断和治疗方式。如果携带LKB1突变的肿瘤生长的尤其迅速，那么具有这种肿瘤的患者或许就可以采用更激烈点的疗法来治疗。
出生时就携带LKB1缺陷版本的人往往会发生Peutz-Jeghers综合症，其主要特征是肠道生长和特定癌症风险的增加。这种基因的非遗传性突变在一些肺癌中存在。这意味着LKB1正常情况下能够抑制肿瘤的形成。突变版本的这种基因则不能起到癌症“刹车”的功能。（Peutz-Jeghers综合症又称皮肤粘膜黑色素斑－胃肠多发性息肉综合症，具有三大特征：多发性胃肠道息肉；特定部位的皮肤及粘膜的黑色素斑点；遗传性。）
在实验中，研究救人员对携带Kras基因的一种缺陷版本的小鼠进行了一系列实验，这种基因缺陷促进肺癌的形成和生长。研究人员追踪了携带LKB1突变的小鼠体内的肺癌的发生，并且将其与两种已经研究较多的肿瘤抑制基因导致的异常情况进行比较。
他们发现，当Kras与突变的肿瘤抑制基因合作时会导致肺癌的发生，并且与突变的LKB1同时存在时更加强烈。缺失LKB1的肿瘤生长的更快，并且比其他情况下更容易扩散。研究表明，LKB1在肺肿瘤的发展重要阶段（起始、正常肺脏细胞向癌细胞的分化和转移）起到重要作用。另外，对人类非小细胞肺组织的一项检测表明，LKB1突变也起到一定作用。
原始出处:
Nature 448, 807-810 (16 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: kwong1@partners.org) or N.E.S. (Email: nes@med.unc.edu) or N.B. (Email: nelbardeesy@partners.org).
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.
