來自法國國立健康與醫(yī)學研究學院的研究人員5月10日表示,，對正常的腎上腺皮質(zhì)細胞以不同的順序?qū)隦as和p53突變體基因,，會產(chǎn)生出不同的腎上腺皮質(zhì)癌的表型，即遺傳變異獲得順序不同會表現(xiàn)出不同的腫瘤表型,。
腎上腺皮質(zhì)癌(ACC)是一種罕見的內(nèi)分泌腫瘤,，往往預(yù)后極差，與此相反,，腎上腺皮質(zhì)瘤為良性腫瘤,，在人群中較為常見。
腎上腺皮質(zhì)瘤是否為一個獨立的腫瘤實體,，亦或是腎上腺皮質(zhì)癌發(fā)展的一個階段性表現(xiàn),，目前仍不明確。
為此,，他們創(chuàng)建了一個預(yù)示腫瘤發(fā)展的老鼠模型,，在這種模型中，正常的腎上腺皮質(zhì)細胞被導入了腎上腺皮質(zhì)瘤中的突變基因,。
癌基因Ras等位基因(H-RasG12V)及p53突變體（p53DD）能夠擾亂p53信號通路而產(chǎn)生腫瘤,，研究發(fā)現(xiàn)，以不同的順序?qū)脒@兩種基因,，會在組織特征,、致瘤性及轉(zhuǎn)移行為表現(xiàn)出顯著差異。
RasG12V及p53DD的成功表達會導致具有轉(zhuǎn)移特性的高度惡性腫瘤,，然而以相反的順序?qū)牒?，促進發(fā)生的僅僅為良性腫瘤。
微陣列分析表明157個基因與癌癥發(fā)展有關(guān),。對比于良性細胞群,，在惡性腫瘤細胞群中，這些基因里有40個基因的表達上調(diào),，117個基因的表達下調(diào),。
研究人員Michal Thomas表示，這是第一次由實驗觀察結(jié)證明腎上腺皮質(zhì)癌是由多級進程發(fā)展而來,，而遺傳變異的獲得順序直接影響了腫瘤的表型,。（生物谷Deepblue編譯）
doi: 10.1371/journal.pgen.1002700
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PMID:
Acquisition Order of Ras and p53 Gene Alterations Defines Distinct Adrenocortical Tumor Phenotypes
Maryline Herbet, Aude Salomon, Jean-Jacques Feige, Michal Thomas.
Sporadic adrenocortical carcinomas (ACC) are rare endocrine neoplasms with a dismal prognosis. By contrast, benign tumors of the adrenal cortex are common in the general population. Whether benign tumors represent a separate entity or are in fact part of a process of tumor progression ultimately leading to an ACC is still an unresolved issue.To this end, we have developed a mouse model of tumor progression by successively transducing genes altered in adrenocortical tumors into normal adrenocortical cells.The introduction in different orders of the oncogenic allele of Ras (H-RasG12V) and the mutant p53DD that disrupts the p53 pathway yielded tumors displaying major differences in histological features, tumorigenicity, and metastatic behavior.Whereas the successive expression of RasG12V and p53DD led to highly malignant tumors with metastatic behavior, reminiscent of those formed after the simultaneous introduction of p53DD and RasG12V, the reverse sequence gave rise only to benign tumors.Microarray profiling revealed that 157 genes related to cancer development and progression were differentially expressed. Of these genes, 40 were up-regulated and 117 were down-regulated in malignant cell populations as compared with benign cell populations.This is the first evidence-based observation that ACC development follows a multistage progression and that the tumor phenotype is directly influenced by the order of acquisition of genetic alterations.
