PNAS：结肠直肠癌中的癌症干细胞被鉴定
斯坦福大学医学院Michael Clarke率领的研究小组最近从结肠直肠癌中鉴别出癌症干细胞，为治疗这些致死性癌症带来新的希望。详细内容刊登于6月4日在线版PNAS。
鉴别新的癌症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。中心主任Irving Weissman博士希望获得一种特异杀死这些癌症干细胞的癌症治疗法，彻底攻克癌症。当今的治疗方法也许能够杀灭大部分肿瘤细胞，但如果有幸存的癌症干细胞，肿瘤会死灰复燃。
早在2003年Clarke于密歇根大学工作时，即在实体瘤（乳腺癌）中首次发现癌症干细胞。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癌症干细胞。这些干细胞如同溪源，不断地分裂产生新肿瘤细胞。尽管其它肿瘤细胞能够分裂，通过它们纯粹体积引发损伤，但生命周期很短，不能维持肿瘤生长。癌症干细胞似乎还与肿瘤转移有关。
结肠直肠癌干细胞高度强调了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自相似组织，意味着存在一种能够治疗所有三种类型细胞的方法。Dalerba在结肠直肠癌干细胞上还发现一种新蛋白——CD166，有望成为鉴别、治疗结肠直肠癌的特定靶标。
结肠直肠癌是美国第二大常见致死性癌症，每年导致5万多人死亡，一般只有在无法医治的最后阶段才能被发现。治疗方法通常有化疗、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强力治疗的患者。
原始出处:
Published online before print June 4, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0703478104
Medical Sciences
Phenotypic characterization of human colorectal cancer stem cells
( CD44 | CD166/ALCAM | tumor differentiation | tumor heterogeneity )
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*Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94304; Oncomed Pharmaceuticals, Inc., Redwood City, CA 94063; Department of Pediatrics, Stanford University, Stanford, CA 94305; ¶Department of Surgery, University of Michigan, Ann Arbor, MI 48109; ||Department of Surgery, Stanford University, Stanford, CA 94305; **Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, 20133 Milano, Italy; and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
Communicated by Irving L. Weissman, Stanford University School of Medicine, Stanford, CA, April 24, 2007 (received for review November 30, 2006)
Abstract
Recent observations indicate that, in several types of human cancer, only a phenotypic subset of cancer cells within each tumor is capable of initiating tumor growth. This functional subset of cancer cells is operationally defined as the "cancer stem cell" (CSC) subset. Here we developed a CSC model for the study of human colorectal cancer (CRC). Solid CRC tissues, either primary tissues collected from surgical specimens or xenografts established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, were disaggregated into single-cell suspensions and analyzed by flow cytometry. Surface markers that displayed intratumor heterogeneous expression among epithelial cancer cells were selected for cell sorting and tumorigenicity experiments. Individual phenotypic cancer cell subsets were purified, and their tumor-initiating properties were investigated by injection in NOD/SCID mice. Our observations indicate that, in six of six human CRC tested, the ability to engraft in vivo in immunodeficient mice was restricted to a minority subpopulation of epithelial cell adhesion molecule (EpCAM)high/CD44+ epithelial cells. Tumors originated from EpCAMhigh/CD44+ cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. Analysis of the surface molecule repertoire of EpCAMhigh/CD44+ cells led to the identification of CD166 as an additional differentially expressed marker, useful for CSC isolation in three of three CRC tested. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation.
相关报道:
Cancer Cell：结肠直肠癌药物结合位点结构和蛋白靶标
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