文章：

肾母细胞瘤：肾脏肿瘤发生与器官发育的联系

Wilms' tumour: connecting tumorigenesis and organ development in the kidney

原文发布日期：2005-08-19

DOI: 10.1038/nrc1696

类型: Review Article

开放获取: 否

要点：

1. Wilms' tumour is a common paediatric malignancy that is derived from pluripotent embryonic renal precursors.
2. WT1 was the first gene shown to be inactivated in Wilms' tumour and it is essential for kidney development. Wt1-knockout mice lack kidneys and WT1 has been implicated in both the survival and differentiation of cells in renal development. Germline WT1 mutations account for Wilms' tumours and urogenital abnormalities in the WAGR (Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) and Denys–Drash syndromes.
3. The two main WT1 isoforms, −KTS and +KTS, have overlapping but distinct functions in renal and gonadal development. These defects are illustrated by Frasier syndrome (lacking the +KTS form) and by mice engineered to lack specific isoforms. Kidneys are abnormal and hypoplastic in the absence of the −KTS form of WT1 whereas the absence of the +KTS form causes defects in the function of glomerular podocytes.
4. Desmoplastic small-round-cell tumour (DSRCT) is a poorly differentiated childhood malignancy in which WT1 acts as a translocation partner with the EWS gene to generate a chimaeric oncogene. Transcriptional targets of this fusion protein include PDGFA, which might contribute to the characteristic stromal reaction observed in these tumours.
5. The WNT pathway, which is critical for kidney development, has been implicated in Wilms' tumour by the identification of activating β-catenin mutations. WT1 and β-catenin mutations are frequently present in the same tumours.
6. The genetic defects that account for most cases of Wilms' tumour remain unknown. Given the intimate connection between Wilms' tumour and renal development, it is likely that novel genes implicated in Wilms' tumour will be important in both tumorigenesis and organogenesis.

要点翻译：

1. 肾母细胞瘤是一种常见的儿童恶性肿瘤，起源于多能性胚胎肾前体细胞。
2. WT1基因是首个被证实在肾母细胞瘤中失活的基因，它对肾脏发育至关重要。Wt1基因敲除小鼠会缺失肾脏，且WT1参与肾脏发育过程中细胞的存活与分化。种系WT1突变可导致WAGR综合征（肾母细胞瘤、无虹膜症、泌尿生殖系统异常和智力障碍）及Denys-Drash综合征中的肾母细胞瘤和泌尿生殖系统异常。
3. 两种主要WT1亚型（-KTS和+KTS）在肾脏和性腺发育中具有重叠但独特的功能。Frasier综合征（缺失+KTS亚型）和经基因改造缺失特定亚型的小鼠模型揭示了这些缺陷：缺乏WT1的-KTS亚型会导致肾脏异常和发育不全，而缺失+KTS亚型则引起肾小球足细胞功能异常。
4. 促结缔组织增生性小圆细胞瘤是一种低分化的儿童恶性肿瘤，其中WT1基因与EWS基因发生易位形成嵌合癌基因。该融合蛋白的转录靶点包括PDGFA，这可能促成该类肿瘤中特征性的间质反应。
5. 对肾脏发育至关重要的WNT通路经证实与肾母细胞瘤相关，研究发现了激活β-连环蛋白的突变。WT1与β-连环蛋白突变常共存于同一肿瘤中。
6. 导致大多数肾母细胞瘤病例的遗传缺陷尚未明确。鉴于肾母细胞瘤与肾脏发育的密切关联，未来发现的肾母细胞瘤相关新基因很可能在肿瘤发生和器官发育中均发挥重要作用。

英文摘要：

Wilms' tumour, or nephroblastoma, is a common childhood tumour that is intimately linked to early kidney development and is often associated with persistent embryonic renal tissue and other kidney abnormalities. WT1, the first gene found to be inactivated in Wilms' tumour, encodes a transcription factor that functions as both a tumour suppressor and a critical regulator of renal organogenesis. Our understanding of the roles of WT1 in tumour formation and organogenesis have advanced in parallel, providing a striking example of the intersection between tumour biology, cellular differentiation and normal organogenesis.

摘要翻译： 

Wilms瘤，即肾母细胞瘤，是一种常见的儿童肿瘤，与早期肾脏发育密切相关，常伴有胚胎性肾组织残留及其他肾脏异常。WT1是首个被发现于Wilms瘤中失活的基因，其编码的转录因子兼具肿瘤抑制功能与肾脏器官发生的关键调控作用。我们对WT1在肿瘤形成与器官发育中作用的认识同步深化，成为肿瘤生物学、细胞分化与正常器官发生交汇的典范。

原文链接：

Wilms' tumour: connecting tumorigenesis and organ development in the kidney