生物谷報(bào)道：斯坦福大學(xué)醫(yī)學(xué)院Michael Clarke率領(lǐng)的研究小組最近從結(jié)腸癌和直腸癌中鑒別出腫瘤干細(xì)胞,，為治療這些致命的癌癥帶來新的希望,。研究結(jié)果發(fā)表在6月12日出版的《美國國家科學(xué)院院刊》（PNAS）上。
早在2003年Clarke于密歇根大學(xué)工作時,，就在乳腺癌中首次發(fā)現(xiàn)腫瘤干細(xì)胞,。2005年轉(zhuǎn)到斯坦福后，他又在頭頸,、胰腺和結(jié)腸直腸腫瘤中發(fā)現(xiàn)腫瘤干細(xì)胞,。這些干細(xì)胞會不斷地分裂產(chǎn)生新腫瘤細(xì)胞。盡管其他腫瘤細(xì)胞能夠分裂,，通過體積膨脹而引起損傷,，但生命周期很短，不能維持腫瘤生長,。腫瘤干細(xì)胞似乎還與腫瘤轉(zhuǎn)移有關(guān),。
鑒別新的腫瘤干細(xì)胞是斯坦福干細(xì)胞生物學(xué)和再生醫(yī)學(xué)中心的主要研究項(xiàng)目之一,。該研究中心的主任Irving Weissman博士希望獲得可以專一地殺死這些腫瘤干細(xì)胞的療法，徹底攻克癌癥,。目前的療法雖然可以殺死大部分腫瘤細(xì)胞,，但如果有幸存的腫瘤干細(xì)胞，腫瘤就會死灰復(fù)燃,。
結(jié)腸直腸癌干細(xì)胞的發(fā)現(xiàn),，強(qiáng)調(diào)了CD44蛋白的重要性，因?yàn)橹坝醒芯孔C實(shí)乳腺癌,、頭頸癌干細(xì)胞的表面也存在CD44蛋白,，文章第一作者Piero Dalerba博士推測這些腫瘤起源相似，意味著這三種類型的腫瘤干細(xì)胞可利用相同的方法治療,。Dalerba在結(jié)腸直腸癌干細(xì)胞上還發(fā)現(xiàn)一種新蛋白——CD166,，將可能成為鑒別、治療結(jié)腸直腸癌的特定靶點(diǎn),。
結(jié)腸直腸癌是美國第二大常見的致死性癌癥,，每年導(dǎo)致5萬多人死亡，通常到了后期才會被發(fā)現(xiàn),。傳統(tǒng)的治療方法包括化療,、放療和外科手術(shù)。結(jié)腸直腸癌外科副教授Andrew Shelton博士說,，很難肯定哪些患者適合哪種治療方法,。Clarke等已經(jīng)在治療效果不佳的患者群中發(fā)現(xiàn)一組開啟/關(guān)閉方式特異的基因，希望在結(jié)腸直腸癌干細(xì)胞中進(jìn)行相似工作,，以區(qū)分出那些需要更多治療的患者,。
Fig. 1. EpCAM/CD44 expression profiles in primary CRC tumors and normal colonic tissues. Analysis of EpCAM/CD44 expression in primary tissues revealed similar profiles among primary CRC tumors (A–C) and normal colorectal epithelium (D–F). Both normal and malignant tissues contained two main cell subsets: EpCAMhigh/CD44+ and EpCAMlow/CD44–. To minimize experimental variability and contributions of genetic background, primary tumors were compared with autologous normal mucosa and analyzed on the same day. EpCAM expression was analyzed by using the B29.1 anti-ESA monoclonal antibody (Biomeda, Foster City, CA). Percentages reported in flow plots indicate the percentage of cells contained within gate P5.
原文出處：
PNAS June 12, 2007; 104 (24)
Piero Dalerba, Scott J. Dylla, In-Kyung Park, Rui Liu, Xinhao Wang, Robert W. Cho, Timothy Hoey, Austin Gurney, Emina H. Huang, Diane M. Simeone, Andrew A. Shelton, Giorgio Parmiani, Chiara Castelli, and Michael F. Clarke
Phenotypic characterization of human colorectal cancer stem cells
PNAS 2007 104: 10158-10163; published online before print June 4 2007, 10.1073/pnas.0703478104 [Abstract] [Full Text] [Figures Only] [PDF] [Supporting Information]
作者簡介：
Michael F. Clarke, M.D.
Honors & Awards
Title Organization Date(s)
Rackham Award University of Michigan
American Society of Clinical Investigation
American Association of Physicians
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Professional Education
Degree Awarding Institution Field of Study Year of Graduation
M.D. Indiana University 1977
B.A. Indiana University 1973
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Research Interests
Dr. Michael F. Clarke is the Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. In addition to his clinical duties in the division of Oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem cells. A central issue in stem cell biology is to understand the mechanisms that regulate self-renewal of hematopoietic stem cells, which are required for hematopoiesis to persist for the lifetime of the animal. Until recently, the molecular mechanisms that regulate adult stem cell self-renewal were not known. His laboratory recently found that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. By investigating the pathways upstream and downstream of Bmi1, the laboratory is actively investigating the molecular pathways that regulate self-renewal.
Cancers arise as a result of a series of genetic mutations. A better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells will help to focus the development of more effective therapies. Solid tumors such as breast cancers contain heterogeneous populations of neoplastic cells. Dr. Clarke’s group has developed a technique that allows the isolation and characterization of tumorigenic and non-tumorigenic populations of cancer cells present in human breast, colon and head and neck cancer tumors. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. This tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. The tumorigenic cells displayed stem cell-like properties in that they were capable of generating new tumors containing additional stem cells as well as regenerating the phenotypically mixed populations of non-tumorigenic cells present in the original tumor. Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of cells. The laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. Dr. Clarke’s laboratory will provide other members of the program with the expertise to identify and isolate cancer stem cells from solid tumors of epithelial origin. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. Differences in self-renewal pathways between normal and malignant stem cells could be targeted by new therapeutic agents to eliminate cancer stem cells.
Recent Publications:
Al-Hajj, M., Wicha, M, Morrison, S.J., Clarke, M.F. Prospective identification and characterization of a tumorigenic breast cancer cell. PNAS 7:3983-8, April 1, 2003.
Park, I.K., Qian, D., Kiel, M., Becker, M.W., Pihalja, M., Weissman, I.L., Morrison, S.J., and Clarke, M.F. Bmi1 is required for adult hematopoietic stem cell self renewal. Nature. 423:302-5, May 15, 2003.
Molofsky A.V., Pardal R., Iwashita T., Park I-K., Clarke, M.F., Morrison S.J. Bmi-1 dependence distinguishes neural stem cell self-renewal from restricted progenitor proliferation. Nature, 425(6961) 962-7, Oct 2003.
Clarke, M.F. Neurobiology: at the root of brain cancer. Nature 432, 281-282, 2004.
Honors:
American Society of Clinical Investigation
Association of American Physicians
Publications
Hosen N, Yamane T, Muijtjens M, Pham K, Clarke MF, Weissman IL "Bmi-1-green fluorescent protein (GFP)-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells." Stem Cells 2007; More Clarke MF, Fuller M "Stem cells and cancer: two faces of eve." Cell 2006; 124: 6: 1111-5 More Akala OO, Clarke MF "Hematopoietic stem cell self-renewal." Curr Opin Genet Dev 2006; More Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM "Cancer Stem Cells--Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells." Cancer Res 2006; More Marshall HS, Gold MS, Gent R, Quinn PJ, Piotto L, Clarke MF, Roberton DM "Ultrasound examination of extensive limb swelling reactions after diphtheria-tetanus-acellular pertussis or reduced-antigen content diphtheria-tetanus-acellular pertussis immunization in preschool-aged children." Pediatrics 2006; 118: 4: 1501-9 More
