Leavitt W W, Evans R W, Hendry W J
Adv Exp Med Biol. 1981;138:63-86. doi: 10.1007/978-1-4615-7192-6_4.
This paper describes a new experimental model system for the induction of endometrial adenocarcinoma in hamster uterus following diethylstilbestrol (DES) treatment of the newborn female. We propose that DES acts as an initiator during early development and that other estrogens act as promoters to stimulate tumor development in the adult uterus. DES directly affects the uterus as was shown by the failure of neonatal ovariectomy to prevent early DES-induced uterine growth. Subsequently, ovarian estrogen secretion from anovulatory, polyfollicular ovaries modifies the DES-altered uterus starting between 20 and 30 days of age and continuing into adult life. Early DES effects on the uterus include stimulation of endometrial cellular differentiation and progesterone receptor production. Permanent changes in uterine collagen, DNA and progesterone receptor content were noted, but the responsiveness of the DES-altered uterus to estrogen and progestin action was not impaired. Morphogenetic changes included an increase in extracellular connective tissue elements and striking alterations in endometrial cell composition such as hyperplasia of luminal and glandular epithelia and a massive inflammatory response in the stroma. Endometrial adenocarcinomas occurred in DES-treated animals in association with exposure to either endogenous estrogen from anovulatory ovaries or exogenous estrogen treatment of the ovariectomized animal. Endometrial tumors had relatively high concentrations of estrogen and progesterone receptors, suggesting a sensitivity to hormone action. Thus, these studies (a) demonstrate the utility of this animal model for the preparation of experimental endometrial tumors, and (b) suggest that DES acts as an initiator to transform uterine cells during early development, and estrogen exposure later in life acts as a promotor to stimulate growth and proliferation of DES-transformed cells.
本文描述了一种新的实验模型系统，用于在新生雌性仓鼠经己烯雌酚（DES）处理后诱导其子宫发生子宫内膜腺癌。我们提出，DES在早期发育过程中起启动子作用，而其他雌激素起促进剂作用，以刺激成年子宫中的肿瘤发展。如新生卵巢切除术未能阻止早期DES诱导的子宫生长所示，DES直接影响子宫。随后，无排卵、多囊卵巢分泌的卵巢雌激素从20至30日龄开始改变DES处理过的子宫，并持续至成年期。DES对子宫的早期影响包括刺激子宫内膜细胞分化和孕激素受体生成。观察到子宫胶原蛋白、DNA和孕激素受体含量发生永久性变化，但DES处理过的子宫对雌激素和孕激素作用的反应性并未受损。形态发生变化包括细胞外结缔组织成分增加以及子宫内膜细胞组成的显著改变，如腔上皮和腺上皮增生以及基质中的大量炎症反应。DES处理的动物发生子宫内膜腺癌与暴露于无排卵卵巢的内源性雌激素或对去卵巢动物进行外源性雌激素处理有关。子宫内膜肿瘤的雌激素和孕激素受体浓度相对较高，表明对激素作用敏感。因此，这些研究（a）证明了该动物模型在制备实验性子宫内膜肿瘤方面的实用性，（b）表明DES在早期发育过程中起启动子作用，促使子宫细胞发生转化，而后期生活中的雌激素暴露起促进剂作用，刺激DES转化细胞的生长和增殖。
