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Multistage carcinogenesis in TSC gene mutant models

TSC 基因突变模型中的多阶段致癌作用

基本信息

批准号：
08264108
负责人：
HINO Okio
金额：
$ 68.48万
依托单位：
Cancer Institute Carcinogenesis
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Cancer is a heritable disorder of somatic cells. Enviroment and heredity both operate in the origin of human cancer. The Tsc2gene mutant (Eker) rat model of hereditary renal carcinoma (RC) is an example of mendelian dominantly inherited predisposition to a specific cancer in an experimantal animal. We used theses unique aniaml models for the study of preblems in carcinogenesis (e.g., tissue/cell-type specific tumorigenesis, multistage carcinogenesis and species-specific difference in tumorigenesis). (1) animal models homologous to human genetic conditions and helpfil toward understanding non-hereditary conditions. (2) opportunity to study earlist lesions. (3) can use strain differences in phenotype to find genetic modifiers of phenotype and possible use for prevention and tratment.The phenotype in human differs from that in the Eker rat, except for the occurrence of RCs (in human, angiomyolipomas are more common), although we found subepedymal and subcortical hamartomas in the Eker rats. Thus, the same gene shows diverse phenotype between species, although we do not have any good explanation for this difference. To elicit insights into species-specific cumorigenesis caused by Tsc2 gene inactivation, we generated a Tsc2 knock out mice. Mice homozygous for Tsc2 mutation developed RCs but no angiomyolipoma, with a complete penetrance as seen in the Eker rat.Thus, TSC genes mutants continues to be a valuable experimental models for understanding the mechanisms of disease, and the development of the therapeutic treatments which can be translated into human patients as well as how enviromental factors interact with cancer susceptibility genes.

癌症是一种可遗传的体细胞疾病。环境和遗传都在人类癌症的起源中起作用。遗传性肾癌（RC）的Tsc 2基因突变（Eker）大鼠模型是实验动物中特定癌症的孟德尔显性遗传易感性的实例。我们使用这些独特的动物模型来研究癌发生中的肿瘤（例如，组织/细胞类型特异性肿瘤发生、多阶段癌发生和肿瘤发生的物种特异性差异）。(1)与人类遗传条件同源的动物模型，有助于理解非遗传性条件。(2)研究早期病变的机会。(3)人类与Eker大鼠的表型不同，除了RCs的发生（在人类中，血管平滑肌脂肪瘤更常见），尽管我们在Eker大鼠中发现了足管下和皮质下错构瘤。因此，相同的基因在物种之间表现出不同的表型，尽管我们对这种差异没有任何好的解释。为了深入了解Tsc 2基因失活引起的物种特异性累积，我们产生了Tsc 2敲除小鼠。Tsc 2突变纯合子小鼠发生了RC，但没有血管平滑肌脂肪瘤，如在Eker大鼠中所见的完全转移。因此，TSC基因突变体仍然是理解疾病机制和开发可转化为人类患者的治疗方法以及环境因素如何与癌症易感基因相互作用的有价值的实验模型。