在上皮組織環(huán)境受損時(shí)促進(jìn)表達(dá)單個(gè)癌基因的細(xì)胞大量生長(zhǎng)的機(jī)制示意圖,。
正常的健康組織通常抑制腫瘤生長(zhǎng)，阻止癌細(xì)胞增殖和轉(zhuǎn)移,。但是這種情形在分子水平上是如何發(fā)生的一直是一個(gè)謎,。如今，研究人員呈現(xiàn)一個(gè)局部環(huán)境如何調(diào)節(jié)和阻止單個(gè)突變細(xì)胞增殖為腫瘤的模型,。
這一發(fā)現(xiàn)發(fā)表在《自然》期刊上,，證實(shí)了以前的研究表明癌癥不只是細(xì)胞中DNA突變堆積的產(chǎn)物，而且還依賴于細(xì)胞所處局部環(huán)境的結(jié)構(gòu),。
美國(guó)耶魯大學(xué)研究皮膚癌的Douglas Brash(未參加這項(xiàng)研究)說(shuō)：“它確實(shí)非常吸引人,。這篇論文證實(shí)癌癥不是細(xì)胞自主引發(fā)的過(guò)程，周圍環(huán)境確實(shí)重要,。”
以前的實(shí)驗(yàn)證實(shí)胚胎能夠抑制腫瘤產(chǎn)生,。比如，在一項(xiàng)經(jīng)典研究中,，注射致瘤性病毒快速誘導(dǎo)孵出的小雞的翅膀長(zhǎng)出腫瘤,，但是在4天大的雞胚胎中則不能誘導(dǎo)腫瘤產(chǎn)生。不過(guò)一直以來(lái)很少有人在組織培養(yǎng)物中進(jìn)行分子水平上的實(shí)驗(yàn)研究這種現(xiàn)象,。
來(lái)自哈佛醫(yī)學(xué)院的Joan Brugge和Cheuk Leung使用人乳腺上皮細(xì)胞的三維細(xì)胞培養(yǎng)物研究表達(dá)單個(gè)癌基因的細(xì)胞在組織類似的環(huán)境中的行為,。研究人員使用病毒載體在三維結(jié)構(gòu)的單個(gè)細(xì)胞中每次過(guò)量表達(dá)一個(gè)已發(fā)現(xiàn)與上皮癌相關(guān)聯(lián)的基因。過(guò)表達(dá)Myc,、一個(gè)重要的轉(zhuǎn)錄因子或者突變激活的干擾細(xì)胞分裂監(jiān)測(cè)點(diǎn)的AKT1都不會(huì)導(dǎo)致細(xì)胞增殖,。Brugge說(shuō)，“我們發(fā)現(xiàn)當(dāng)單個(gè)細(xì)胞處于正常的限制生長(zhǎng)的結(jié)構(gòu)環(huán)境下大多數(shù)癌基因不能夠擴(kuò)增,。”
但是過(guò)表達(dá)ERBB2---一種在30%乳腺瘤中發(fā)生擴(kuò)增的基因編碼的細(xì)胞受體---的細(xì)胞移動(dòng)到組織培養(yǎng)物的中間,，即稱作腔(lumen)的開放空間。在那里,，單個(gè)突變的細(xì)胞不受正常的周邊環(huán)境影響而進(jìn)行增殖,。
研究人員通過(guò)進(jìn)一步實(shí)驗(yàn)發(fā)現(xiàn)ERBB2表達(dá)影響胞外基質(zhì)蛋白，從而破壞局部的細(xì)胞-基質(zhì)附著和允許細(xì)胞沖破束縛進(jìn)入腔中不受限制的空間環(huán)境,。當(dāng)表達(dá)ERBB2的細(xì)胞移動(dòng)到腔中的能力受阻時(shí),，它與相鄰的細(xì)胞呆在一起而不再能夠進(jìn)行增殖。他們也發(fā)現(xiàn)只需通過(guò)破壞組織中細(xì)胞之間的連接,，表達(dá)包括激活的AKT1在內(nèi)的之前是良性的其他癌基因的突變細(xì)胞能夠移動(dòng)進(jìn)入腔中并發(fā)生增殖,。Bras說(shuō)，“與突變細(xì)胞相鄰的細(xì)胞的地理環(huán)境影響著突變的細(xì)胞是否能夠移動(dòng)到組織中不同的部分,。”
接下來(lái),，Brugge計(jì)劃研究成熟的相鄰細(xì)胞如何阻止單個(gè)突變的細(xì)胞發(fā)生增殖以及環(huán)境中其他因素如免疫細(xì)胞是否影響突變細(xì)胞的命運(yùn)。她說(shuō)，“我們想知道正常條件下局部環(huán)境結(jié)構(gòu)抑制效應(yīng)的性質(zhì),。” (生物谷：towersimper編譯)
doi:10.1038/nature10826
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PMID:
Outgrowth of single oncogene-expressing cells from suppressive epithelial environments
Cheuk T. Leung & Joan S. Brugge
Tumorigenesis is a clonal evolution process that is initiated from single cells within otherwise histologically normal tissue1. It is unclear how single, sporadic mutant cells that have sustained oncogenic alterations evolve within a tightly regulated tissue environment. Here we investigated the effects of inducing oncogene expression in single cells in organotypic mammary acini as a model to elucidate the processes by which oncogenic alterations initiate clonal progression from organized epithelial environments. Sporadic cells induced to overexpress oncogenes that specifically perturb cell-cycle checkpoints (for example, E7 from human papilloma virus 16, and cyclin D1), deregulate Myc transcription or activate AKT signalling remained quiescent within growth-arrested acini. By contrast, single cells that overexpress ERBB2 initiated a cellular cascade involving cell translocation from the epithelial layer, as well as luminal outgrowth that is characteristic of neoplastic progression in early-stage epithelial tumours. In addition, ERBB2-mediated cell translocation to the lumen was found to depend on extracellular-regulated kinase and matrix metalloproteinase activities, and genetic alterations that perturb local cell–matrix adhesion drove cell translocation. We also provide evidence that luminal cell translocation may drive clonal selection by promoting either the death or the expansion of quiescent oncogene-expressing cells, depending on whether the pre-existing alterations allow anchorage-independent survival and growth. Our data show that the initial outgrowth of single oncogene-expressing cells from organized epithelial structures is a highly regulated process, and we propose that a cell translocation mechanism allows sporadic mutant cells to evade suppressive micro-environments and elicits clonal selection for survival and proliferative expansion outside the native niches of these cells.
