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首页> 外文期刊>Nature >Prominin 1 Marks Intestinal Stem Cells That Are Susceptible To Neoplastic Transformation
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Prominin 1 Marks Intestinal Stem Cells That Are Susceptible To Neoplastic Transformation

机译：Prominin 1标记易患肿瘤转化的肠道干细胞

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Cancer stem cells are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, for example, prominin 1 (PROM1, also called CD133). What remains unclear is whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that reacquire stem cell properties during tumour formation. Answering this question will require knowledge of whether normal stem cells are susceptible to cancer-causing mutations; however, this has proved difficult to test because the identity of most adult tissue stem cells is not known. Here, using an inducible Cre, nuclear LacZ reporter allele knocked into the Proml locus (Proml~(C-L)), we show that Proml is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Proml~(+/C-L) mice containing the Rosa26-YFP reporter allele showed that Proml~+ cells are located at the base of crypts in the small intestine, co-express Lgr5 (ref. 2), generate the entire intestinal epithelium, and are therefore the small intestinal stem cell. Proml was reported recently to mark cancer stem cells of human intestinal tumours that arise frequently as a consequence of aberrant wingless (Wnt) signalling. Activation of endogenous Wnt signalling in Proml~(+/C-L) mice containing a Cre-dependent mutant allele of P-catenin (Ctnnbl~(lox(ex3))) resulted in a gross disruption of crypt architecture and a disproportionate expansion of Proml~+ cells at the crypt base. Lineage tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intra-epithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Proml~+ cells in these mice, only 7% of tumour cells retained Proml expression. Our data indicate that Proml marks stem cells in the adult small intestine that are susceptible to transformation into tumours retaining a fraction of mutant Proml~+ tumour cells.
机译：癌症干细胞与正常干细胞非常相似：它们都具有自我更新功能，具有多能性，并表达常见的表面标志物，例如prominin 1（PROM1，也称为CD133）。尚不清楚的是，癌症干细胞是突变干细胞的直接后代，还是在肿瘤形成过程中重新获得干细胞特性的更成熟的细胞。要回答这个问题，将需要了解正常干细胞是否易受致癌突变的影响。但是，由于大多数成年组织干细胞的身份尚不清楚，因此很难测试。在这里，我们使用诱导型Cre，核LacZ记者等位基因敲入Proml位点（Proml〜（C-L）），我们证明了Proml在各种发育和成年组织中表达。含有Rosa26-YFP报告基因等位基因的成年Proml〜（+ / CL）小鼠的谱系追踪研究表明，Proml〜+细胞位于小肠隐窝的底部，共表达Lgr5（参考文献2），产生整个肠上皮，因此是小肠干细胞。最近有报道称Proml标记人肠道肿瘤的癌症干细胞，这些人的干细胞由于无翼（Wnt）信号异常而频繁出现。 Proml〜（+ / CL）小鼠中含有P-catenin的Cre依赖性突变等位基因（Ctnnbl〜（lox（ex3）））的内源性Wnt信号的激活导致了隐窝结构的彻底破坏和Proml〜的过度扩展+隐窝底部的细胞。谱系追踪证明，这些细胞的后代用肿瘤组织代替了整个小肠的粘膜，其特征是局灶性高度上皮内瘤变和隐窝腺瘤形成。尽管在这些小鼠中所有肿瘤细胞均起源于Proml〜+细胞，但只有7％的肿瘤细胞保留了Proml表达。我们的数据表明，Proml标志着成年小肠中的干细胞，该干细胞易于转化为保留一部分突变Proml〜+肿瘤细胞的肿瘤。

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