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斯坦福大学医学院Michael Clarke率领的研究小组最近从结肠癌和直肠癌中鉴别出肿瘤干细胞，为治疗这些致命的癌症带来新的希望。研究结果发表在6月12日出版的《美国国家科学院院刊》（PNAS）上。
早在2003年Clarke于密歇根大学工作时，就在乳腺癌中首次发现肿瘤干细胞。2005年转到斯坦福后，他又在头颈、胰腺和结肠直肠肿瘤中发现肿瘤干细胞。这些干细胞会不断地分裂产生新肿瘤细胞。尽管其他肿瘤细胞能够分裂，通过体积膨胀而引起损伤，但生命周期很短，不能维持肿瘤生长。肿瘤干细胞似乎还与肿瘤转移有关。
鉴别新的肿瘤干细胞是斯坦福干细胞生物学和再生医学中心的主要研究项目之一。该研究中心的主任Irving Weissman博士希望获得可以专一地杀死这些肿瘤干细胞的疗法，彻底攻克癌症。目前的疗法虽然可以杀死大部分肿瘤细胞，但如果有幸存的肿瘤干细胞，肿瘤就会死灰复燃。
结肠直肠癌干细胞的发现，强调了CD44蛋白的重要性，因为之前有研究证实乳腺癌、头颈癌干细胞的表面也存在CD44蛋白，文章第一作者Piero Dalerba博士推测这些肿瘤起源相似，意味着这三种类型的肿瘤干细胞可利用相同的方法治疗。Dalerba在结肠直肠癌干细胞上还发现一种新蛋白——CD166，将可能成为鉴别、治疗结肠直肠癌的特定靶点。
结肠直肠癌是美国第二大常见的致死性癌症，每年导致5万多人死亡，通常到了后期才会被发现。传统的治疗方法包括化疗、放疗和外科手术。结肠直肠癌外科副教授Andrew Shelton博士说，很难肯定哪些患者适合哪种治疗方法。Clarke等已经在治疗效果不佳的患者群中发现一组开启/关闭方式特异的基因，希望在结肠直肠癌干细胞中进行相似工作，以区分出那些需要更多治疗的患者。
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.
原文出处：
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]
作者简介：
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 |
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发表于 2007-7-12 09:10:14