在一項(xiàng)新的研究中,英國(guó)約克大學(xué)科學(xué)家們發(fā)現(xiàn)促進(jìn)前列腺癌產(chǎn)生的驅(qū)動(dòng)力：從人前列腺癌中提取出的干細(xì)胞發(fā)生DNA重排(DNA re-alignment)從而誘導(dǎo)癌癥產(chǎn)生.這就為開發(fā)出靶向前列腺癌干細(xì)胞(prostate cancer stem cell)的藥物奠定基礎(chǔ),同時(shí)也有望開發(fā)出更加有效的療法來(lái)抵抗這種疾病的根源.相關(guān)研究結(jié)果于2013年3月27日發(fā)表在Nature Communications期刊上,論文標(biāo)題為"Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells".
論文通信作者、約克大學(xué)癌癥研究中心主任Norman Maitland教授和他的研究團(tuán)隊(duì)于2005年首次分離出前列腺癌干細(xì)胞.盡管癌癥中其他的癌細(xì)胞能夠被當(dāng)前的療法殺死,但是癌干細(xì)胞能夠逃避這些療法的作用,從而導(dǎo)致癌癥復(fù)發(fā).從那以后,該研究團(tuán)隊(duì)就一直在尋找是哪些分子讓這些細(xì)胞擴(kuò)散,、存活以及抵抗諸如放療和化療之類的進(jìn)取性治療.
Maitland教授說(shuō),"這項(xiàng)發(fā)現(xiàn)標(biāo)志著我們對(duì)實(shí)體瘤是如何開始產(chǎn)生的理解發(fā)生根本性轉(zhuǎn)變.人們常認(rèn)為作為疾病根源的癌干細(xì)胞是由于健康干細(xì)胞發(fā)生差錯(cuò)而產(chǎn)生的,比如某些控制機(jī)制被關(guān)閉從而允許這些細(xì)胞持續(xù)增殖,從而侵入周圍的組織."
"諸如白血病之類的血癌中,DNA重排在染色體易位過(guò)程期間發(fā)生,從而導(dǎo)致促進(jìn)癌癥發(fā)展的蛋白突變體產(chǎn)生.盡管類似的重排最近已在實(shí)體瘤中發(fā)現(xiàn)過(guò),但是在此之前,這些重排從不認(rèn)為會(huì)在干細(xì)胞中發(fā)生.我們的這項(xiàng)研究挑戰(zhàn)了這種看法."
在這項(xiàng)研究中,研究人員在前列腺癌干細(xì)胞中發(fā)現(xiàn)了這些異常的基因事件,即DNA重排,并且證實(shí)它們導(dǎo)致細(xì)胞內(nèi)一種特異性的癌癥相關(guān)基因ERG不適當(dāng)?shù)丶せ?他們認(rèn)為這種激活觸發(fā)這種癌干細(xì)胞更加頻繁地自我更新.
Maitland教授繼續(xù)說(shuō)道,"這些癌干細(xì)胞不接受前列腺中存在的正?？刂?變得非常自私：它們以犧牲周圍的正常細(xì)胞為代價(jià)進(jìn)行頻繁地增殖,從而確保這些基因事件持續(xù)存在,并且代代相傳.這種過(guò)程似乎是啟動(dòng)前列腺癌產(chǎn)生所必需的."
這項(xiàng)發(fā)現(xiàn)有助于人們更好地理解前列腺癌是如何發(fā)生的.人們?nèi)缃窨赡苣軌蛲ㄟ^(guò)特異性地靶向鑒定出的基因來(lái)開發(fā)出新的療法以便殺死接受化療后仍然存活下來(lái)的癌干細(xì)胞,同時(shí)不傷害健康的細(xì)胞.（生物谷Bioon.com）
doi:10.1038/ncomms2627
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Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells
Euan S. Polson,John L. Lewis,Hamza Celik,Vincent M. Mann,Michael J. Stower,Matthew S. Simms,Greta Rodrigues,Anne T. Collins & Norman J. Maitland
While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells. Moreover, we show that in the prostate epithelial hierarchy from both normal and tumour tissues, TMPRSS2 transcription is subjected to tight monoallelic regulation, which is retained upon asymmetric division and relaxed during epithelial cell differentiation. The presence and expression of TMPRSS2/ERG in prostate stem cells would provide ERG-driven survival advantages, allowing maintenance of this mutated genotype.
