Kubo Y, Klimek F, Kikuchi Y, Bannasch P, Hino O
Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Cancer Res. 1995 Mar 1;55(5):989-90.
Hereditary renal cell carcinomas invariably develop by the age of 1 year in Eker rats. At the histological level, renal cell carcinomas develop through multiple stages from early preneoplastic lesions (e.g., phenotypically altered tubules) to adenomas. We previously reported that ionizing radiation induces additional tumors (large adenomas and carcinomas) in a linear dose-response relationship and that loss of heterozygosity (LOH) at chromosome 10, where the predisposing tuberous sclerosis (Tsc2) gene is localized, was found in the renal cell carcinomas which developed from hybrid F1 rats carrying the Eker mutation, indicating that in heterozygotes two events (one inherited, one somatic) are necessary to produce at least large adenomas and carcinomas. This study was designed to examine LOH in the earliest preneoplastic lesions, using a laser microdissection procedure. We could accurately dissect single altered renal tubules out of freeze-dried sections and clearly detected LOH in 4 of 19 altered tubules (21%). This is the first demonstration of LOH in single renal tubules. Our present results support the theory of a second, somatic mutation (second hit) as rate-limiting step of renal carcinogenesis in the Eker rat model of dominantly inherited cancer and the tumor suppressor nature of the Tsc2 gene function.
在艾克大鼠中，遗传性肾细胞癌在1岁时必然会发生。在组织学水平上，肾细胞癌从早期的癌前病变（如表型改变的肾小管）发展到腺瘤，经历多个阶段。我们之前报道过，电离辐射以线性剂量反应关系诱导额外的肿瘤（大腺瘤和癌），并且在携带艾克突变的杂交F1大鼠发生的肾细胞癌中，发现位于10号染色体上的易感结节性硬化症（Tsc2）基因所在区域存在杂合性缺失（LOH），这表明在杂合子中，至少产生大腺瘤和癌需要两个事件（一个是遗传的，一个是体细胞的）。本研究旨在使用激光显微切割技术检测最早的癌前病变中的杂合性缺失。我们能够从冻干切片中准确地分离出单个改变的肾小管，并在19个改变的肾小管中的4个（21%）中清楚地检测到杂合性缺失。这是首次在单个肾小管中证明杂合性缺失。我们目前的结果支持在显性遗传癌症的艾克大鼠模型中，第二次体细胞突变（二次打击）作为肾致癌作用限速步骤的理论，以及Tsc2基因功能的肿瘤抑制性质。
