在本周的《自然》（Nature）上發(fā)表了2個(gè)有關(guān)基因的研究報(bào)告,，有助于開發(fā)抗癌新藥或新的藥物配伍,。
美國紐約Howard Hughes醫(yī)學(xué)研究所的Massague博士發(fā)現(xiàn),，有4個(gè)基因協(xié)同作用可以幫助癌癥惡化和轉(zhuǎn)移,，分別是EREG,、MMP-1,、MMP-2和COS-2,，戲稱為“基因四人幫”,。動(dòng)物實(shí)驗(yàn)直接說明了這4個(gè)基因在腫瘤轉(zhuǎn)移時(shí)的協(xié)同作用，把敲除4個(gè)基因的細(xì)胞直接注射入小鼠,，細(xì)胞就停滯在肺泡壁,。提示細(xì)胞可能利用這4個(gè)基因打開肺泡的細(xì)胞壁，然后開始生長,。腫瘤在轉(zhuǎn)移前有很高的治愈率,，一旦發(fā)生轉(zhuǎn)移則很難治愈。所以Massague博士領(lǐng)導(dǎo)的研究小組在體外進(jìn)行了基因表達(dá)抑制試驗(yàn),，希望能發(fā)現(xiàn)新的治療方法,。實(shí)驗(yàn)表明，抑制4個(gè)基因中的某一個(gè)作用較小,，同時(shí)關(guān)閉全部4個(gè)基因?qū)⑼耆种颇[瘤增長和阻止其轉(zhuǎn)移,。實(shí)際上，研究者已經(jīng)注意到服用阿司匹林和Celebrek等對(duì)COS-2基因有影響或抑制劑的人患某些癌癥的幾率減小,。輝瑞公司（NYSE:PFE）的Celebrek以及施貴寶（NYSE: BMY）和ImClone聯(lián)合開發(fā)的Erbitux就是靶向作用于4個(gè)基因中的2個(gè),。Massague博士在小鼠中聯(lián)合使用Celebrek和Erbitux，發(fā)現(xiàn)效果顯著,。這對(duì)于發(fā)現(xiàn)新的聯(lián)合治療法有很大的指導(dǎo)意義,。
另一個(gè)研究是由美國德州大學(xué)西南醫(yī)學(xué)中心的Michael White博士領(lǐng)導(dǎo)進(jìn)行的。他們發(fā)現(xiàn)了87個(gè)基因,，如果把它們關(guān)閉了的話,，腫瘤細(xì)胞對(duì)化療的敏感性大大增加。White博士在人全基因組范圍篩選使肺癌細(xì)胞對(duì)紫杉醇敏感的基因,，結(jié)果發(fā)現(xiàn)了87個(gè)基因,，在他們被關(guān)閉時(shí)，用低于正常劑量1000倍的紫杉醇就能殺死癌細(xì)胞,。據(jù)White博士說,，有些上市藥物已經(jīng)靶向針對(duì)這些基因,，有些在研藥物也以這些基因?yàn)榘形铩Ｋ麄兊难芯坑兄诮忉尀槭裁从袝r(shí)化療的療效很差,，特別是肺癌,。這些基因的發(fā)現(xiàn)將對(duì)醫(yī)生選擇高毒性低劑量的藥物有指導(dǎo)意義?；熓?ldquo;盲目”的,，對(duì)患者造成很大副作用，確定影響化療效果的基因并開發(fā)出抑制他們的藥物是個(gè)性化治療的良好基礎(chǔ),。
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: [email protected]).
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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: [email protected]).
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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.
