Maitland N J, Brown K W, Poirier V, Shaw A P, Williams J
Department of Pathology, University of Bristol, Medical School, U.K.
Anticancer Res. 1989 Sep-Oct;9(5):1417-26.
Wilms' tumour is an embryonal kidney tumour which exists in an hereditary and sporadic form. Apart from its obvious importance as a model for renal development and differentiation, the tumour has recently been exploited as an example of the action of tumour suppressor genes (or anti-oncogenes). The latter genes are characterised by a somatic loss of genetic information in tumour development, specifically from the short arm of human chromosome 11 in Wilms' tumour. To further study the developmental aspects of the tumour we have established in vitro cell cultures from tumour tissues, which, unlike the majority of Wilms' tumour cell lines, have been genotyped according to their chromosome 11 gene status and their antigen expression patterns, compared to the original normal kidney and tumour tissues. The cell cultures exist both as primary and secondary cultures, and their limited life span in culture has been extended by transfection of SV40 large T antigen. The mechanism of tumour suppression by the Wilms' locus has been explored by producing cell hybrids between the immortalised kidney cells, and an "indicator cell" (HeLa), whose chromosome 11 genotypes have been monitored in vivo and in vitro by restriction fragment length polymorphisms. Non-random patterns of inheritance of the mutant allele have also been investigated, both in tumour tissue and in syndromes, like the Beckwith-Wiedemann Syndrome, which pre-dispose to development of Wilms' tumour (and other embryonal tumours). It is also apparent that allele-specific methylation occurs in Wilms' tumour tissues, probably resulting in changes of gene expression patterns. Significant elevation of transcription of the N-myc oncogene was detected in the blastemal cells of the most malignant Wilms' tumours, whereas a marked decrease in the expression of HLA class I, at both RNA and protein levels was observed in the same cells. Wilm's tumour provides a clear illustration of the requirement for a combination of dominantly and recessively acting genes, in order to produce a malignant embryonal tumour.
肾母细胞瘤是一种胚胎性肾肿瘤，有遗传性和散发性两种形式。除了作为肾脏发育和分化模型具有明显重要性外，该肿瘤最近还被用作肿瘤抑制基因（或抗癌基因）作用的一个例子。后一类基因的特征是在肿瘤发生过程中出现遗传信息的体细胞丢失，在肾母细胞瘤中具体表现为人类11号染色体短臂的丢失。为了进一步研究该肿瘤的发育方面，我们从肿瘤组织建立了体外细胞培养物，与大多数肾母细胞瘤细胞系不同，这些细胞培养物已根据其11号染色体基因状态及其抗原表达模式进行了基因分型，并与原始正常肾脏和肿瘤组织进行了比较。细胞培养物既有原代培养物也有传代培养物，通过转染SV40大T抗原延长了它们在培养中的有限寿命。通过在永生化肾细胞与一种“指示细胞”（HeLa）之间产生细胞杂种，探索了肾母细胞瘤位点的肿瘤抑制机制，该指示细胞的11号染色体基因型已通过限制性片段长度多态性在体内和体外进行监测。还研究了突变等位基因在肿瘤组织和诸如贝克威思-维德曼综合征等综合征中的非随机遗传模式，这些综合征易患肾母细胞瘤（和其他胚胎性肿瘤）。同样明显的是，肾母细胞瘤组织中发生了等位基因特异性甲基化，这可能导致基因表达模式的改变。在最恶性的肾母细胞瘤的胚基细胞中检测到N-myc癌基因转录显著升高，而在同一细胞中观察到HLA I类分子在RNA和蛋白质水平的表达均明显降低。肾母细胞瘤清楚地说明了需要显性和隐性作用基因相结合才能产生恶性胚胎性肿瘤。
