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腾讯登录Stem Cells ：研究发现人黑色素瘤干细胞的存在
| 导读 | 癌症干细胞具有以下三种能力：分化、自我更新和种植定位成为肿瘤。由于这些干细胞能抵抗化疗，许多研究人员断定其在癌症复发中起关键作用。最近发表在<em>Stem Cells</em>杂志上的一项由美国科罗拉多大学癌症中心领导完成的研究表明，黑色素瘤细胞具备癌症干细胞样特性，黑色素瘤细胞上存在干细胞的标记物ALDH酶，靶向高ALDH表达细胞的新疗法或许能清除这些最危险的癌症促发细... |
癌症干细胞具有以下三种能力：分化、自我更新和种植定位成为肿瘤。由于这些干细胞能抵抗化疗，许多研究人员断定其在癌症复发中起关键作用。最近发表在<em>Stem Cells</em>杂志上的一项由美国科罗拉多大学癌症中心领导完成的研究表明，黑色素瘤细胞具备癌症干细胞样特性，黑色素瘤细胞上存在干细胞的标记物ALDH酶，靶向高ALDH表达细胞的新疗法或许能清除这些最危险的癌症促发细胞。
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CU医学院皮肤性病科副教授Mayumi Fujita医学博士说：我们已经知道在其他类型的癌症中，ALDH是作为干细胞的标记物所存在，但在黑色素瘤中，并未发现ALDH的存在。到目前为止，ALDH的功能在很大程度上仍是未知的。
Fujita研究小组移植ALDH +和ALDH-黑色素瘤细胞到动物模型中，发现种植ALDH +细胞的动物更易得癌症，即ALDH +细胞更具备致瘤性。在相同的ALDH +细胞中，沉默了产生该蛋白ALDH的基因后发现，敲除降低ALDH表达的黑色素瘤细胞出现死亡，失去了在动物模型中形成肿瘤的能力。在细胞培养中，沉默ALDH基因亦使得黑色素瘤细胞对现有的化疗更加敏感。研究小组还分析了人类肿瘤样品，他们发现不同亚群的这些ALDH +细胞，组成了患者原发肿瘤组织的0.1-0.2％左右。在转移性黑色素瘤样本中，侵略性越强，ALDH +细胞的比例更高，甚至超过了10％。
在这些相同的ALDH +细胞上，我们发现干细胞的标记物是上调的，细胞分化是下调的。除了这些线索外，在原发肿瘤中ALDH +细胞能产生异质性细胞类型，这意味着ALDH +细胞具有自我更新的能力，ALDH +细胞具备成为癌症干细胞的第三个条件即分化能力。
这项研究还揭示了ALDH基因及其蛋白是如何作用制造出一个干细胞样特性的细胞的。Fujita说：ALDH制造出一个癌干细胞样特性的细胞的方法之一是通过维甲酸信号通路。蛋白ALDH导致的视黄酸生成过剩，它反过来又结合到细胞的核受体上，影响许多细胞的基因的表达例如参与调节细胞存活、修复的基因。Fujita说：我们的希望是，无论是对乙醛脱氢酶（ALDH）的水平或其他信号途径，我们都可以干预这一信号，使用一种新的药物，以使得黑色素瘤干细胞对化疗药物更敏感可能提高肿瘤治疗的成效。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120823152417.htm" target="_blank">Human Melanoma Stem Cells Identified</a>
<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082509352580.gif" alt="" width="115" height="150" border="0" />
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<a title="" href="http://dx.doi.org/10.1002/stem.1193" target="_blank">doi:10.1002/stem.1193</a>
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<br/><strong>ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets.</strong><br/>
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.
<br/>来源：生物谷
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CU医学院皮肤性病科副教授Mayumi Fujita医学博士说：我们已经知道在其他类型的癌症中，ALDH是作为干细胞的标记物所存在，但在黑色素瘤中，并未发现ALDH的存在。到目前为止，ALDH的功能在很大程度上仍是未知的。
Fujita研究小组移植ALDH +和ALDH-黑色素瘤细胞到动物模型中，发现种植ALDH +细胞的动物更易得癌症，即ALDH +细胞更具备致瘤性。在相同的ALDH +细胞中，沉默了产生该蛋白ALDH的基因后发现，敲除降低ALDH表达的黑色素瘤细胞出现死亡，失去了在动物模型中形成肿瘤的能力。在细胞培养中，沉默ALDH基因亦使得黑色素瘤细胞对现有的化疗更加敏感。研究小组还分析了人类肿瘤样品，他们发现不同亚群的这些ALDH +细胞，组成了患者原发肿瘤组织的0.1-0.2％左右。在转移性黑色素瘤样本中，侵略性越强，ALDH +细胞的比例更高，甚至超过了10％。
在这些相同的ALDH +细胞上，我们发现干细胞的标记物是上调的，细胞分化是下调的。除了这些线索外，在原发肿瘤中ALDH +细胞能产生异质性细胞类型，这意味着ALDH +细胞具有自我更新的能力，ALDH +细胞具备成为癌症干细胞的第三个条件即分化能力。
这项研究还揭示了ALDH基因及其蛋白是如何作用制造出一个干细胞样特性的细胞的。Fujita说：ALDH制造出一个癌干细胞样特性的细胞的方法之一是通过维甲酸信号通路。蛋白ALDH导致的视黄酸生成过剩，它反过来又结合到细胞的核受体上，影响许多细胞的基因的表达例如参与调节细胞存活、修复的基因。Fujita说：我们的希望是，无论是对乙醛脱氢酶（ALDH）的水平或其他信号途径，我们都可以干预这一信号，使用一种新的药物，以使得黑色素瘤干细胞对化疗药物更敏感可能提高肿瘤治疗的成效。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120823152417.htm" target="_blank">Human Melanoma Stem Cells Identified</a>
<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082509352580.gif" alt="" width="115" height="150" border="0" />
<div id="ztload">
<div>
<div>
<a title="" href="http://dx.doi.org/10.1002/stem.1193" target="_blank">doi:10.1002/stem.1193</a>
PMC:
PMID:
</div>
<div>
<br/><strong>ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets.</strong><br/>
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.
<br/>来源：生物谷
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