Wolf D C, Goldsworthy T L, Donner E M, Harden R, Fitzpatrick B, Everitt J I
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
Carcinogenesis. 1998 Nov;19(11):2043-7. doi: 10.1093/carcin/19.11.2043.
Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.
已知激素影响会在人类和实验动物模型中影响肾细胞癌的发展。我们使用结节性硬化症2（Tsc2）杂合突变（Eker）大鼠来检验雌激素治疗或大鼠卵巢切除术调节肾肿瘤发展的假说，在这种大鼠中，种系突变使动物易患肾细胞肿瘤。将两个月大的雌性野生型和Eker大鼠进行卵巢切除或假手术，并皮下植入含安慰剂或5毫克17β-雌二醇的药粒，持续6或10个月。在8或12个月龄时对大鼠进行检查，此时对肾肿瘤和癌前病灶的数量进行定量，并评估肾病的严重程度。与预期相反，长期雌激素治疗增强了遗传性肾细胞肿瘤的发展，与未治疗的Eker大鼠相比，癌前和肿瘤性肾病变的数量增加了两倍。卵巢切除的Eker大鼠的肾病变比未处理的对照组少33%。在两个时间点的野生型大鼠中均未发现肿瘤或癌前病变。雌激素治疗增加了野生型和Eker大鼠肾病的严重程度，而卵巢切除术对肾病性变化具有保护作用。虽然雌激素不是大鼠肾致癌物，但给Eker大鼠施用时会增强遗传性肾细胞肿瘤的发展。Tsc2基因座发生突变的杂合Eker大鼠提供了一个很好的模型，可用于研究遗传和激素因素如何促进肾细胞肿瘤的发展，并了解遗传易感性对肾细胞癌发展的影响。
