生物谷：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PNAS杂志上。
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。（引自生命经纬）
原始出处:
Published online before print June 4, 2007, 10.1073/pnas.0703478104
PNAS | June 12, 2007 | vol. 104 | no. 24 | 10158-10163
BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Phenotypic characterization of human colorectal cancer stem cells
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*,,
*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)
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.
CD44 | CD166/ALCAM | tumor differentiation | tumor heterogeneity
A growing body of evidence is increasingly lending support to the idea that human cancer can be considered as a stem cell disease (1–3). According to the "cancer stem cell" (CSC) theory, tumors are not to be viewed as simple monoclonal expansions of transformed cells, but rather as complex tissues where abnormal growth is driven by a minority, pathological CSC pool that, on the one hand, has acquired tumor-related features such as uncontrolled growth and the ability to form metastases and, on the other hand, maintains its inherent capacity to self-renew and differentiate into a phenotypically heterogeneous, although aberrant, progeny. This hypothesis is supported by three key experimental observations initially performed on human acute myeloid leukemia (4) and subsequently extended to human solid tumors (5, 6): (i) Only a minority of cancer cells within each tumor is endowed with tumorigenic potential when transplanted into immunodeficient mice, (ii) tumorigenic cancer cells are characterized by a distinctive profile of surface markers and can be differentially and reproducibly isolated from nontumorigenic ones by flow cytometry, and (iii) tumors grown from tumorigenic cells contain mixed populations of both tumorigenic and nontumorigenic cancer cells, thus re-creating the full phenotypic heterogeneity of the parent tumor.
Currently, cancer cell subpopulations selectively endowed with tumorigenic potential are operationally defined as CSCs and have been prospectively identified from selected types of human solid cancer, such as breast (5), brain (6, 7), colon (8, 9), head and neck (10), and pancreatic cancer (11). However, the CSC working model is still being subjected to intense debate (12), and data published on colorectal cancer (CRC) indicate that a subgroup of primary CRC is likely to be negative for the marker currently used for isolation of colorectal CSCs (Co-CSCs) (9). In the present study, we developed an alternative, very robust protocol for the isolation of human Co-CSCs.
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