生物谷：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PNAS雜志上,。
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，因為之前有研究證實(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,。（引自生命經(jīng)緯）
原始出處:
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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