在本周的《自然》（Nature）上发表了2个有关基因的研究报告，有助于开发抗癌新药或新的药物配伍。
美国纽约Howard Hughes医学研究所的Massague博士发现，有4个基因协同作用可以帮助癌症恶化和转移，分别是EREG、MMP-1、MMP-2和COS-2，戏称为“基因四人帮”。动物实验直接说明了这4个基因在肿瘤转移时的协同作用，把敲除4个基因的细胞直接注射入小鼠，细胞就停滞在肺泡壁。提示细胞可能利用这4个基因打开肺泡的细胞壁，然后开始生长。肿瘤在转移前有很高的治愈率，一旦发生转移则很难治愈。所以Massague博士领导的研究小组在体外进行了基因表达抑制试验，希望能发现新的治疗方法。实验表明，抑制4个基因中的某一个作用较小，同时关闭全部4个基因将完全抑制肿瘤增长和阻止其转移。实际上，研究者已经注意到服用阿司匹林和Celebrek等对COS-2基因有影响或抑制剂的人患某些癌症的几率减小。辉瑞公司（NYSE:PFE）的Celebrek以及施贵宝（NYSE: BMY）和ImClone联合开发的Erbitux就是靶向作用于4个基因中的2个。Massague博士在小鼠中联合使用Celebrek和Erbitux，发现效果显著。这对于发现新的联合治疗法有很大的指导意义。
另一个研究是由美国德州大学西南医学中心的Michael White博士领导进行的。他们发现了87个基因，如果把它们关闭了的话，肿瘤细胞对化疗的敏感性大大增加。White博士在人全基因组范围筛选使肺癌细胞对紫杉醇敏感的基因，结果发现了87个基因，在他们被关闭时，用低于正常剂量1000倍的紫杉醇就能杀死癌细胞。据White博士说，有些上市药物已经靶向针对这些基因，有些在研药物也以这些基因为靶物。他们的研究有助于解释为什么有时化疗的疗效很差，特别是肺癌。这些基因的发现将对医生选择高毒性低剂量的药物有指导意义。化疗是“盲目”的，对患者造成很大副作用，确定影响化疗效果的基因并开发出抑制他们的药物是个性化治疗的良好基础。
部分英文原文：
1、 Nature 446, 765-770 (12 April 2007) | doi:10.1038/nature05760; Received 19 December 2006; Accepted 21 March 2007
Mediators of vascular remodelling co-opted for sequential steps in lung metastasis
Gaorav P. Gupta1,5, Don X. Nguyen1,5, Anne C. Chiang1,2, Paula D. Bos1, Juliet Y. Kim1, Cristina Nadal1,6, Roger R. Gomis1,6, Katia Manova-Todorova3 & Joan Massagué1,4
Cancer Biology and Genetics Program,
Department of Medicine,
Molecular Cytology Core Facility, and,
Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
These authors contributed equally to this work.
Present addresses: Hemato-Oncology Institute, Hospital Clinic de Barcelona, 08036 Barcelona, Spain (C.N.); Oncology Programme, Institute for Research in Biomedecine, Barcelona Science Park and University of Barcelona, 08028 Barcelona, Spain (R.R.G.).
Correspondence to: Joan Massagué1,4 Correspondence and requests for materials should be addressed to J.M. (Email: j-massague@ski.mskcc.org).
Top of page
Abstract
Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.
2、 Nature 446, 815-819 (12 April 2007) | doi:10.1038/nature05697; Received 26 October 2006; Accepted 20 February 2007
Synthetic lethal screen identification of chemosensitizer loci in cancer cells
Angelique W. Whitehurst1, Brian O. Bodemann1, Jessica Cardenas1, Deborah Ferguson2, Luc Girard3, Michael Peyton3, John D. Minna3,4, Carolyn Michnoff5, Weihua Hao5, Michael G. Roth5, Xian-Jin Xie4,6 & Michael A. White1,4
Department of Cell Biology,
Reata Pharmaceuticals,
Hamon Center for Therapeutic Oncology Research,
Simmons Cancer Center,
Department of Biochemistry, and,
Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Correspondence to: Michael A. White1,4 Correspondence and requests for materials should be addressed to M.A.W. (Email: michael.white@utsouthwestern.edu).
Top of page
Abundant evidence suggests that a unifying principle governing the molecular pathology of cancer is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis1. Anomalous proteins engaged in support of this tumorigenic regulatory environment most probably represent optimal intervention targets in a heterogeneous population of cancer cells. The advent of RNA-mediated interference (RNAi)-based functional genomics provides the opportunity to derive unbiased comprehensive collections of validated gene targets supporting critical biological systems outside the framework of preconceived notions of mechanistic relationships. We have combined a high-throughput cell-based one-well/one-gene screening platform with a genome-wide synthetic library of chemically synthesized small interfering RNAs for systematic interrogation of the molecular underpinnings of cancer cell chemoresponsiveness. NCI-H1155, a human non-small-cell lung cancer line, was employed in a paclitaxel-dependent synthetic lethal screen designed to identify gene targets that specifically reduce cell viability in the presence of otherwise sublethal concentrations of paclitaxel. Using a stringent objective statistical algorithm to reduce false discovery rates below 5%, we isolated a panel of 87 genes that represent major focal points of the autonomous response of cancer cells to the abrogation of microtubule dynamics. Here we show that several of these targets sensitize lung cancer cells to paclitaxel concentrations 1,000-fold lower than otherwise required for a significant response, and we identify mechanistic relationships between cancer-associated aberrant gene expression programmes and the basic cellular machinery required for robust mitotic progression.
