據(jù)《癌癥細(xì)胞》（Cancer Cell）雜志2007年3月13日報道,，Dana-Farber癌癥研究所最新的研究對“腫瘤干細(xì)胞”假說提出了質(zhì)疑,。該假說認(rèn)為，腫瘤組織內(nèi)有少量可以自我復(fù)制的腫瘤干細(xì)胞,，腫瘤干細(xì)胞在乳腺癌變過程中和癌癥復(fù)發(fā)中起主導(dǎo)作用,，清除腫瘤干細(xì)胞就可治愈癌癥。
文章報道,，科學(xué)家已經(jīng)從一個乳腺癌組織標(biāo)本中分離出兩個遺傳背景不同的細(xì)胞群,，其中之一就是其他科學(xué)家堅信存在的乳腺癌腫瘤干細(xì)胞。文章資深作者Kornelia Polyak 指出,，“如果全部的乳腺癌細(xì)胞源自同一個癌干細(xì)胞,，那么僅需用一種藥就可以治愈該病。但是根據(jù)實驗結(jié)果,，我們推測,，乳腺癌細(xì)胞是來自一種干細(xì)胞樣的祖細(xì)胞，是由這類細(xì)胞分化為遺傳背景不均一的腫瘤細(xì)胞,，因此必須對這兩類細(xì)胞都進行治療,。”這兩類細(xì)胞（干細(xì)胞樣祖細(xì)胞和癌細(xì)胞），或許還有其它的,，都與乳腺癌的癌變過程有關(guān),。研究者對這兩類細(xì)胞進行基因掃描分析后，發(fā)現(xiàn)所謂的“腫瘤干細(xì)胞”與正常的干細(xì)胞很像,，是由一個激活的分子通路誘導(dǎo)產(chǎn)生的,。乳腺癌患者如果含有大量這種干細(xì)胞樣細(xì)胞，其癌癥復(fù)發(fā)的機率是相當(dāng)高的,。但這種情況也有其積極的一面,，因為這種腫瘤干細(xì)胞樣細(xì)胞存在異常的信號活化通路，如目前已知道的TGF-β1信號轉(zhuǎn)導(dǎo)通路，而實驗已發(fā)現(xiàn)可以抑制信號活化通路的藥物,。因此,，臨床上使用這些信號活化通路抑制藥物，再加上其它治療,，估計會改善由這類細(xì)胞產(chǎn)生的乳腺癌,。
腫瘤的形成是源于細(xì)胞的克隆演變還是腫瘤干細(xì)胞分化？細(xì)胞克隆演變是一個解釋腫瘤形成的理論模型,，該模型認(rèn)為腫瘤細(xì)胞是經(jīng)過長期的克隆演變篩選出來的：正常的細(xì)胞出現(xiàn)突變,，產(chǎn)生了異常的子代細(xì)胞克隆，而各個子代細(xì)胞又突變產(chǎn)生更加異常的子代細(xì)胞克隆,，如此循環(huán),，最終會產(chǎn)生大量的遺傳背景不均一的細(xì)胞克隆,，正常細(xì)胞變成了癌細(xì)胞,，至此腫瘤就形成了。目前另外還有一個解釋腫瘤形成的理論,，其觀點是單一的某種異常類型的成人干細(xì)胞產(chǎn)生并促使了腫瘤的形成,，所以最終形成的腫瘤其細(xì)胞的遺傳背景是均一的，乳腺癌的產(chǎn)生就是這樣,。腫瘤干細(xì)胞假說認(rèn)為,，用藥物很難將這些少量的可自我復(fù)制的腫瘤干細(xì)胞殺滅，也許腫瘤干細(xì)胞這種耐藥性可解釋為何經(jīng)過成功治療的乳腺癌患者仍會經(jīng)常復(fù)發(fā),。2003年科學(xué)家已從患者腫瘤組織里分離出所謂的乳腺癌腫瘤干細(xì)胞,，其細(xì)胞表面分子CD44認(rèn)為是腫瘤干細(xì)胞特異性分子，但CD44分子也是正常乳腺細(xì)胞的分子標(biāo)志,。CD44陽性細(xì)胞輸入給免疫缺陷的小鼠后可形成乳腺腫瘤,。科學(xué)家還發(fā)現(xiàn)與之緊密相關(guān)的細(xì)胞為CD22陽性,，懷疑其是CD44陽性細(xì)胞產(chǎn)生的子代細(xì)胞,。
Polyak和Michail Shipitsin領(lǐng)導(dǎo)的研究小組采用基因掃描技術(shù)分析了這兩類細(xì)胞的關(guān)系。他們分別從正常乳腺上皮,、胸腔積液,、乳腺癌原位癌患者標(biāo)本中分離出CD24陽性和CD44陽性細(xì)胞，再制備成各自的基因庫進行 基因掃描,。最后的實驗結(jié)果與細(xì)胞克隆演化模型理論更相符合,，也就是說，CD24陽性細(xì)胞和CD44陽性細(xì)胞在遺傳背景上并非等同,，僅是相似而已,，但按腫瘤干細(xì)胞假說的觀點，CD44陽性細(xì)胞為腫瘤干細(xì)胞，CD24陽性細(xì)胞是其子代細(xì)胞,，那么兩者的遺傳背景應(yīng)該是一致的,。“盡管CD44陽性細(xì)胞可表達(dá)多種干細(xì)胞分子標(biāo)志，但是,，由同一腫瘤組織分離得到的CD24陽性和 CD44陽性細(xì)胞兩者在遺傳背景上是有差異的,，這一結(jié)果對腫瘤干細(xì)胞假說構(gòu)成了質(zhì)疑，同時支持細(xì)胞克隆演化模型,，因為該理論可以很好地解釋腫瘤異質(zhì)性這一現(xiàn)象,。”作者在論文中寫道。
Polyak研究小組進一步發(fā)現(xiàn),，活化的TGF-β1信號轉(zhuǎn)導(dǎo)通路可誘導(dǎo)CD44陽性細(xì)胞產(chǎn)生,，而CD24陽性細(xì)胞則沒有這種現(xiàn)象，為此,，他們說,，“臨床上，腫瘤細(xì)胞表達(dá)CD44分子較表達(dá)CD24的預(yù)后更差,，但是,，CD44陽性細(xì)胞反而可以提供TGF-β1信號轉(zhuǎn)導(dǎo)通路為靶點進行治療。”
部分英文原文：
Volume 11, Issue 3 , 13 March 2007, Pages 259-273
Molecular Definition of Breast Tumor Heterogeneity
Michail Shipitsin1, 3, Lauren L. Campbell1, 5, Pedram Argani6, Stanislawa Weremowicz4, 10, Noga Bloushtain-Qimron1, Jun Yao1, 3, Tatiana Nikolskaya7, 8, Tatiana Serebryiskaya7, 8, Rameen Beroukhim1, 3, Min Hu1, 3, Marc K. Halushka6, Saraswati Sukumar6, Leroy M. Parker1, 3, Karen S. Anderson1, 3, Lyndsay N. Harris1, 3, Judy E. Garber1, 3, Andrea L. Richardson4, 10, Stuart J. Schnitt4, 11, Yuri Nikolsky7, Rebecca S. Gelman2, 9 and Kornelia Polyak1, 3, 5,
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
3Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
4Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
5Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA
6Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
7GeneGo, Inc., St. Joseph, MI 49085, USA
8Vavilov Institute for General Genetics, Moscow B333, 117809, Russia
9Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
10Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
11Department of Pathology, Beth-Israel Deaconess Medical Center, Boston, MA 02115, USA
Received 11 August 2006; revised 20 November 2006; accepted 16 January 2007. Published: March 12, 2007. Available online 12 March 2007.
Summary
Cells with distinct phenotypes including stem-cell-like properties have been proposed to exist in normal human mammary epithelium and breast carcinomas, but their detailed molecular characteristics and clinical significance are unclear. We determined gene expression and genetic profiles of cells purified from cancerous and normal breast tissue using markers previously associated with stem-cell-like properties. CD24+ and CD44+ cells from individual tumors were clonally related but not always identical. CD44+ cell-specific genes included many known stem-cell markers and correlated with decreased patient survival. The TGF-β pathway was specifically active in CD44+ cancer cells, where its inhibition induced a more epithelial phenotype. Our data suggest prognostic relevance of CD44+ cells and therapeutic targeting of distinct tumor cell populations.
Author Keywords: CELLCYCLE
