2012年8月25日 訊 /生物谷BIOON/ --癌癥干細(xì)胞具有以下三種能力：分化、自我更新和種植定位成為腫瘤,。由于這些干細(xì)胞能抵抗化療,，許多研究人員斷定其在癌癥復(fù)發(fā)中起關(guān)鍵作用。最近發(fā)表在Stem Cells雜志上的一項(xiàng)由美國科羅拉多大學(xué)癌癥中心領(lǐng)導(dǎo)完成的研究表明,，黑色素瘤細(xì)胞具備癌癥干細(xì)胞樣特性,，黑色素瘤細(xì)胞上存在干細(xì)胞的標(biāo)記物ALDH酶，靶向高ALDH表達(dá)細(xì)胞的新療法或許能清除這些最危險(xiǎn)的癌癥促發(fā)細(xì)胞,。
CU醫(yī)學(xué)院皮膚性病科副教授Mayumi Fujita醫(yī)學(xué)博士說：我們已經(jīng)知道在其他類型的癌癥中,，ALDH是作為干細(xì)胞的標(biāo)記物所存在，但在黑色素瘤中,，并未發(fā)現(xiàn)ALDH的存在,。到目前為止,，ALDH的功能在很大程度上仍是未知的。
Fujita研究小組移植ALDH +和ALDH-黑色素瘤細(xì)胞到動物模型中,，發(fā)現(xiàn)種植ALDH +細(xì)胞的動物更易得癌癥,，即ALDH +細(xì)胞更具備致瘤性。在相同的ALDH +細(xì)胞中,，沉默了產(chǎn)生該蛋白ALDH的基因后發(fā)現(xiàn),，敲除降低ALDH表達(dá)的黑色素瘤細(xì)胞出現(xiàn)死亡，失去了在動物模型中形成腫瘤的能力,。在細(xì)胞培養(yǎng)中,，沉默ALDH基因亦使得黑色素瘤細(xì)胞對現(xiàn)有的化療更加敏感。研究小組還分析了人類腫瘤樣品,，他們發(fā)現(xiàn)不同亞群的這些ALDH +細(xì)胞,，組成了患者原發(fā)腫瘤組織的0.1-0.2％左右。在轉(zhuǎn)移性黑色素瘤樣本中,，侵略性越強(qiáng),，ALDH +細(xì)胞的比例更高，甚至超過了10％,。
在這些相同的ALDH +細(xì)胞上,，我們發(fā)現(xiàn)干細(xì)胞的標(biāo)記物是上調(diào)的，細(xì)胞分化是下調(diào)的,。除了這些線索外,，在原發(fā)腫瘤中ALDH +細(xì)胞能產(chǎn)生異質(zhì)性細(xì)胞類型，這意味著ALDH +細(xì)胞具有自我更新的能力,，ALDH +細(xì)胞具備成為癌癥干細(xì)胞的第三個(gè)條件即分化能力,。
這項(xiàng)研究還揭示了ALDH基因及其蛋白是如何作用制造出一個(gè)干細(xì)胞樣特性的細(xì)胞的。Fujita說：ALDH制造出一個(gè)癌干細(xì)胞樣特性的細(xì)胞的方法之一是通過維甲酸信號通路,。蛋白ALDH導(dǎo)致的視黃酸生成過剩,，它反過來又結(jié)合到細(xì)胞的核受體上，影響許多細(xì)胞的基因的表達(dá)例如參與調(diào)節(jié)細(xì)胞存活,、修復(fù)的基因,。Fujita說：我們的希望是，無論是對乙醛脫氫酶（ALDH）的水平或其他信號途徑,，我們都可以干預(yù)這一信號,，使用一種新的藥物，以使得黑色素瘤干細(xì)胞對化療藥物更敏感可能提高腫瘤治療的成效,。（生物谷：Bioon.com）
doi:10.1002/stem.1193
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ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets.
Yuchun Luo, Katiuscia Dallaglio, Ying Chen, William A Robinson, Steven E Robinson, Martin D McCarter, Jianbin Wang, Rene Gonzalez, David C Thompson, David A Norris, Dennis R Roop, Vasilis Vasiliou, Mayumi Fujita.
Although the concept of cancer stem cells (CSCs) is well accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In the present study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into NOD/SCID mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis and decreased cell viability in vitro and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
