鼎鼎大名的Robert A.Weinberg教授身上籠罩著一道道絢麗的光環(huán)：美國(guó)科學(xué)院院士,，世界著名Whitehead研究所創(chuàng)始人之一,，他曾發(fā)現(xiàn)了第一個(gè)人類癌基因Ras和第一個(gè)抑癌基因Rb,，他的一系列杰出研究工作已經(jīng)成為腫瘤研究領(lǐng)域乃至整個(gè)醫(yī)學(xué)生物學(xué)領(lǐng)域的重要里程碑,。
Weinberg教授撰寫(xiě)的兩篇關(guān)于腫瘤細(xì)胞十大特征的綜述文章,，常年是Cell雜志最受關(guān)注的論文之一,，也被多次引用,，近期他與其他幾位科學(xué)家一道,，完成了題為“Cell plasticity and heterogeneity in cancer”的綜述性文章，詳細(xì)介紹了癌細(xì)胞發(fā)生發(fā)展的新模型,。
癌癥異質(zhì)性是惡性腫瘤重要特征之一,，這種異質(zhì)性可以表現(xiàn)在腫瘤分化水平及腫瘤功能水平上，出現(xiàn)異質(zhì)性的抗原表達(dá)或出現(xiàn)不同生物特性細(xì)胞亞群,。這種腫瘤異質(zhì)性特性往往給腫瘤的研究和治療帶來(lái)極大的困難,。
癌癥異質(zhì)性是由癌細(xì)胞中遺傳和表觀遺傳差異造成的，這些因素共同作用,，導(dǎo)致了帶有不同表型的疾病表象出現(xiàn),，目前關(guān)于癌癥發(fā)展和擴(kuò)散有兩種模型，也就是克隆進(jìn)化模型,，以及癌癥干細(xì)胞模型,。
在這篇綜述中，研究人員探討了這兩種模型,。其中克隆進(jìn)化（clonal evolution）模型認(rèn)為,，腫瘤起源于正常細(xì)胞，這些細(xì)胞突變并產(chǎn)生了異常的后代,，而后代細(xì)胞又發(fā)生突變,，形成大量的變異癌細(xì)胞。
而癌癥干細(xì)胞假說(shuō)則認(rèn)為,，腫瘤是被一個(gè)單一的,、成體干細(xì)胞異常型所引發(fā)和驅(qū)動(dòng),。而且，正常干細(xì)胞功能必須的幾個(gè)途徑和基因在癌細(xì)胞中被活化,，在腫瘤形成過(guò)程中起到關(guān)鍵作用,。極個(gè)別能促進(jìn)癌癥形成的自我更新干細(xì)胞很難被殺死，并且它們頑強(qiáng)的生命力可以解釋為什么腫瘤常常在成功治療后仍然會(huì)復(fù)發(fā),。
研究人員指出,，前者模型認(rèn)為微環(huán)境選擇壓力導(dǎo)致了連續(xù)突變的積累，出現(xiàn)了腫瘤,，后者則表明具有相同遺傳背景的癌細(xì)胞能根據(jù)其致癌潛力,，分層組織，癌癥干細(xì)胞位于這一層級(jí)的頂端,，具有腫瘤起始和擴(kuò)散的能力,。
后面這種模型的一大特點(diǎn)就是其明顯的單向性，即癌癥干細(xì)胞進(jìn)行對(duì)稱分裂,，來(lái)補(bǔ)充干細(xì)胞池,，也進(jìn)行不對(duì)稱分裂，產(chǎn)生具有低致癌性的子細(xì)胞（非癌癥干細(xì)胞）,。
然而不斷出現(xiàn)的研究新成果又提出了一種新型致癌性模型,，就是在非癌癥干細(xì)胞和癌癥干細(xì)胞之間存在相當(dāng)大的可塑性，如非癌癥干細(xì)胞可以重新恢復(fù)癌癥干細(xì)胞的表型,。這些發(fā)現(xiàn)表明,，一些腫瘤可能就遵循著可塑性癌癥干細(xì)胞模型，可以進(jìn)行雙向轉(zhuǎn)換,，這很常見(jiàn),，也是致癌性的重要組成部分。
目前已有越來(lái)越多的證據(jù)支持癌細(xì)胞的可塑性,，尤其是研究發(fā)現(xiàn)侵襲性的癌癥干細(xì)胞會(huì)在一個(gè)腫瘤中再次出現(xiàn),。鑒于目前不少治療焦點(diǎn)都靶定在癌癥干細(xì)胞上,，研究人員也進(jìn)一步探討了非癌癥干細(xì)胞-癌癥干細(xì)胞轉(zhuǎn)換對(duì)于未來(lái)治療的影響,。
除此之外，需要提出提醒的是,，Weinberg教授研究組此前的一篇文章：Ras Modulates Myc Activity to Repress Thrombospondin-1 Expression and Increase Tumor Angiogenesis,，由于數(shù)據(jù)圖片處理方面的問(wèn)題被撤回，如有這方面的引用和相關(guān)研究,，請(qǐng)多注意,。(生物谷Bioon.com)
doi: 10.1373/clinchem.2012.184655
PMC:
PMID:
Cell Plasticity and Heterogeneity in Cancer
Nemanja D. Marjanovic1, Robert A. Weinberg1,2 and Christine L. Chaffer1,*
BACKGROUND: Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models. CONTENT: The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity. SUMMARY: Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies.
