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【Nature Reviews Cancer】转移的机制：上皮-间质转化（EMT）的癌细胞有干细胞功能

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Metastasis: Regressing to self-renewal
Nature Reviews Cancer 8, 483 (July 2008) | doi:10.1038/nrc2423
Gemma K. Alderton

The epithelial–mesenchymal transition (EMT) is a developmental process that appears to be adopted by tumour cells to confer malignant traits such as invasiveness, survival and motility. However, how malignant cells that have undergone an EMT are able to propagate tumour growth at distant sites has remained unclear. Sendurai Mani, Robert Weinberg and colleagues now provide evidence that the EMT also confers stem cell-like properties.

Using immortalized human mammary epithelial cells (HMECs) Mani and colleagues induced an EMT through ectopic expression of the development-associated transcription factors TWIST or SNAIL, or through exposure to transforming growth factor 1 (TGF1). The cells were fractionated by flow cytometry based on the expression of the cell surface markers CD44 and CD24. They found that cells that had undergone an EMT exhibited CD44high/CD24low expression, the fraction usually associated with mammary epithelial stem cells. Consistently, they found that HMECs that had undergone an EMT formed 30–40-fold more mammospheres in suspension culture, which indicates the acquisition of mammary epithelial stem cell properties. Next, they showed that these cells also acquired self-renewal properties and that they were multipotent — capable of producing both luminal and basal cell lineages. Matrigel culture also revealed that HMECs that had undergone an EMT were capable of forming complex secondary structures comparable to normal mammary ducts. Collectively, these data indicate that the EMT confers stem-like properties to non-transformed HMECs.

So, do stem cells exhibit EMT markers? The authors assessed the RNA expression profiles of monolayer cultures of fractionated HMECs (that had not undergone experimentally induced EMT) and found that CD44high/CD24low-expressing cells exhibited an EMT-associated gene expression profile. Moreover, they showed that mouse mammary stem cells (isolated using the homologous CD49fhigh/CD24med antigen phenotype) exhibited self-renewal properties and expressed markers associated with passage through the EMT.

Is this relevant to breast cancer? Using serial analysis of gene expression on three reduction mammoplasty and five breast carcinoma samples, the authors found that CD44high/CD24lowcells expressed high levels of mRNAs encoding mesenchymal markers. This indicates that mammary epithelial stem cells can be generated from more differentiated cell populations that undergo an EMT and that the EMT could produce the so-called 'cancer stem cells' from more differentiated tumour cells. Indeed, ERBB2-transformed HMECs that have undergone an EMT formed at least 10-fold more tumour spheres and colonies in soft agar than those that had not undergone an EMT and the expression of SNAIL or TWIST in HRAS-V12-transformed HMECs increased the number of tumour-initiating cells by about twofold, as determined by xenograft experiments.

Mani, Weinberg and colleagues suggest that the EMT might be a pathway that confers both metastatic and self-renewal properties to breast tumour cells, enabling disseminated tumour cells to produce macroscopic growths at sites of metastasis.

http://www.nature.com/nrc/journal/v8/n7/full/nrc2423.html

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2008-06-24 21:50 浏览 : 9064 回复 : 20

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kejia0422 编辑于 2008-09-04 23:08

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本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。

2008-06-26 05:43

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Metastasis: Regressing to self-renewal
上皮-间质转化与转移：干细胞特性之回归

The epithelial–mesenchymal transition (EMT) is a developmental process that appears to be adopted by tumour cells to confer malignant traits such as invasiveness, survival and motility. However, how malignant cells that have undergone an EMT are able to propagate tumour growth at distant sites has remained unclear. Sendurai Mani, Robert Weinberg and colleagues now provide evidence that the EMT also confers stem cell-like properties.

上皮-间质转化(epithelial–mesenchymal transitions,EMT)显然是一个被肿瘤细胞利用，从而产生了符合恶性肿瘤特性的，如侵润，存活和并迁移的一个发展（发育）历程。然而，转化为EMT 的恶性肿瘤细胞是如何在远处生长繁殖仍不清楚。最近，Sendurai Mani, Robert Weinberg 和同事们发现了EMT带有了干细胞样属性的依据。

Using immortalized human mammary epithelial cells (HMECs) Mani and colleagues induced an EMT through ectopic expression of the development-associated transcription factors TWIST or SNAIL, or through exposure to transforming growth factor 1 (TGF1). The cells were fractionated by flow cytometry based on the expression of the cell surface markers CD44 and CD24. They found that cells that had undergone an EMT exhibited CD44high/CD24low expression, the fraction usually associated with mammary epithelial stem cells.

Mani和同事通过外源表达发育相关转录因子TWIST 或SNAIL，或通过TGF1处理，成功诱导永生化乳腺上皮细胞(HMECs)成为EMT。这些EMT细胞根据细胞表面标志CD44和CD24进行流式分选。他们发现这些转化的EMT细胞带有CD44高表达，CD24低表达，与通常的乳腺上皮干细胞的分类标志一致。

Consistently, they found that HMECs that had undergone an EMT formed 30–40-fold more mammospheres in suspension culture, which indicates the acquisition of mammary epithelial stem cell properties.

同样的，他们发现转化为EMT的HMECs在悬浮培养液下形成30-40倍的更多的微球体，这提示它们已具有乳腺上皮干细胞和特性。

Next, they showed that these cells also acquired self-renewal properties and that they were multipotent — capable of producing both luminal and basal cell lineages. Matrigel culture also revealed that HMECs that had undergone an EMT were capable of forming complex secondary structures comparable to normal mammary ducts. Collectively, these data indicate that the EMT confers stem-like properties to non-transformed HMECs.

进一步，他们发现这些细胞也有自我更新的属性，并属于多向潜能 — 能产生乳腺导管腔上皮细胞（luminal cell）、基底细胞（basal cell）。Matrigel培养也发现转化为EMT的HMECs细胞与正常乳腺导管细胞类似也形成复杂的二级结构。综合分析，这些数据提示这些EMT与非转化的HMECs相比，已具有干细胞样特性。

So, do stem cells exhibit EMT markers? The authors assessed the RNA expression profiles of monolayer cultures of fractionated HMECs (that had not undergone experimentally induced EMT) and found that CD44high/CD24low-expressing cells exhibited an EMT-associated gene expression profile. Moreover, they showed that mouse mammary stem cells (isolated using the homologous CD49fhigh/CD24med antigen phenotype) exhibited self-renewal properties and expressed markers associated with passage through the EMT.

然后，下一个问题是干细胞是否具有EMT的标志？作者分析了单层培养的分选的（没有经过诱导转化为EMT实验）的HMECs 细胞的RNA表达谱，并发现CD44高/CD24低表达细胞展示了EMT相关的基因表达谱。而且，它们，他们也发现了鼠乳腺干细胞（用CD49fhigh/CD24med表型分离）也具有自我更新属性，并表达EMT相关的标志。

Is this relevant to breast cancer? Using serial analysis of gene expression on three reduction mammoplasty and five breast carcinoma samples, the authors found that CD44high/CD24lowcells expressed high levels of mRNAs encoding mesenchymal markers.

这是否与乳腺癌相关呢？通过对3个乳房缩小整形术（reduction mammoplasty）和5个乳腺癌标本进行系列基因表达分析，作者发现CD44高表达，CD24低表达细胞高水平的表达间质细胞标志的mRNA。

This indicates that mammary epithelial stem cells can be generated from more differentiated cell populations that undergo an EMT and that the EMT could produce the so-called 'cancer stem cells' from more differentiated tumour cells.

这提示乳腺上皮干细胞能从分化的细胞群EMT转化时产生，EMT能从相对分化的肿瘤细胞中生成被称为“肿瘤干细胞”的细胞。

Indeed, ERBB2-transformed HMECs that have undergone an EMT formed at least 10-fold more tumour spheres and colonies in soft agar than those that had not undergone an EMT and the expression of SNAIL or TWIST in HRAS-V12-transformed HMECs increased the number of tumour-initiating cells by about twofold, as determined by xenograft experiments.

实际上，，ERBB2转化并经历EMT转变的HMECs细胞，与无EMT转化的相比，形成至少10倍更多的肿瘤球，和软琼脂上的克隆，同时在移植瘤实验中发现，用HRAS-V12表达SNAIL 或TWIST 转化HMECs 细胞能形成约两倍的致瘤细胞。

Mani, Weinberg and colleagues suggest that the EMT might be a pathway that confers both metastatic and self-renewal properties to breast tumour cells, enabling disseminated tumour cells to produce macroscopic growths at sites of metastasis.

Mani, Weinberg 和同事认为EMT可能是乳腺细胞同时具有转移和干细胞特性的通路，导致转移的肿瘤细胞在转移位置成长为肉眼可见的肿瘤。

2008-06-29 05:23

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上皮-间质转化与转移：干细胞特性之回归

上皮-间质转化(epithelial–mesenchymal transitions,EMT)显然是一个被肿瘤细胞利用，从而产生了符合恶性肿瘤特性的，如侵润，存活和并迁移的一个发展（发育）历程。然而，转化为EMT 的恶性肿瘤细胞是如何在远处生长繁殖仍不清楚。最近，Sendurai Mani, Robert Weinberg 和同事们发现了EMT带有了干细胞样属性的依据。

Mani和同事通过外源表达发育相关转录因子TWIST 或SNAIL，或通过TGF1处理，成功诱导永生化乳腺上皮细胞(HMECs)成为EMT。这些EMT细胞根据细胞表面标志CD44和CD24进行流式分选。他们发现这些转化的EMT细胞带有CD44高表达，CD24低表达，与通常的乳腺上皮干细胞的分类标志一致。

同样的，他们发现转化为EMT的HMECs在悬浮培养液下形成30-40倍的更多的微球体，这提示它们已具有乳腺上皮干细胞和特性。

进一步，他们发现这些细胞也有自我更新的属性，并属于多向潜能 — 能产生乳腺导管腔上皮细胞（luminal cell）、基底细胞（basal cell）。Matrigel培养也发现转化为EMT的HMECs细胞与正常乳腺导管细胞类似也形成复杂的二级结构。综合分析，这些数据提示这些EMT与非转化的HMECs相比，已具有干细胞样特性。

然后，下一个问题是干细胞是否具有EMT的标志？作者分析了单层培养的分选的（没有经过诱导转化为EMT实验）的HMECs 细胞的RNA表达谱，并发现CD44高/CD24低表达细胞展示了EMT相关的基因表达谱。而且，它们，他们也发现了鼠乳腺干细胞（用CD49fhigh/CD24med表型分离）也具有自我更新属性，并表达EMT相关的标志。

这是否与乳腺癌相关呢？通过对3个乳房缩小整形术（reduction mammoplasty）和5个乳腺癌标本进行系列基因表达分析，作者发现CD44高表达，CD24低表达细胞高水平的表达间质细胞标志的mRNA。
这提示乳腺上皮干细胞能从分化的细胞群EMT转化时产生，EMT能从相对分化的肿瘤细胞中生成被称为“肿瘤干细胞”的细胞。

实际上，，ERBB2转化并经历EMT转变的HMECs细胞，与无EMT转化的相比，形成至少10倍更多的肿瘤球，和软琼脂上的克隆，同时在移植瘤实验中发现，用HRAS-V12表达SNAIL 或TWIST 转化HMECs 细胞能形成约两倍的致瘤细胞。

Mani, Weinberg 和同事认为EMT可能是乳腺细胞同时具有转移和干细胞特性的通路，导致转移的肿瘤细胞在转移位置成长为肉眼可见的肿瘤。

2008-06-29 05:24

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