Multistage carcinogenesis in TSC gene mutant models

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Tsc2基因突变(Eker)大鼠模型是实验动物中孟德尔遗传易感性的一个例子。我们使用这些独特的动物模型来研究肿瘤发生中的问题(例如，组织/细胞类型的特异性肿瘤发生、多阶段癌症发生和肿瘤发生的物种特异性差异)。(1)与人类遗传疾病同源的动物模型，有助于了解非遗传疾病。(2)研究早期病变的机会。(3)可以利用表型上的菌株差异来寻找表型的遗传修饰物，并可能用于预防和治疗。人类的表型与Eker大鼠不同，但RCS的发生(在人类中，血管肌脂肪瘤更常见)，尽管我们在Eker大鼠中发现了生殖器下和皮质下错构瘤。因此，相同的基因在不同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很好的解释。为了深入了解TSC2基因失活引起的物种特异性内源性发育，我们产生了一只TSC2基因敲除小鼠。TSC2突变纯合子小鼠出现RCS，但没有血管肌脂肪瘤，与Eker大鼠一样，完全外显。因此，TSC基因突变仍然是理解疾病机制、开发可移植到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。

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.