Stewart Sherri L, Querec Troy D, Ochman Alexander R, Gruver Briana N, Bao Rudi, Babb James S, Wong Thang S, Koutroukides Theodoros, Pinnola Aaron D, Klein-Szanto Andres, Hamilton Thomas C, Patriotis Christos
Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Cancer Res. 2004 Nov 15;64(22):8177-83. doi: 10.1158/0008-5472.CAN-04-1702.
Animal models of ovarian cancer are crucial for understanding the pathogenesis of the disease and for testing new treatment strategies. A model of ovarian carcinogenesis in the rat was modified and improved to yield ovarian preneoplastic and neoplastic lesions that pathogenetically resemble human ovarian cancer. A significantly lower dose (2 to 5 mug per ovary) of 7,12-dimethylbenz(a)anthracene (DMBA) was applied to the one ovary to maximally preserve its structural integrity. DMBA-induced mutagenesis was additionally combined with repetitive gonadotropin hormone stimulation to induce multiple cycles of active proliferation of the ovarian surface epithelium. Animals were treated in three arms of different doses of DMBA alone or followed by hormone administration. Comparison of the DMBA-treated ovaries with the contralateral control organs revealed the presence of epithelial cell origin lesions at morphologically distinct stages of preneoplasia and neoplasia. Their histopathology and path of dissemination to other organs are very similar to human ovarian cancer. Hormone cotreatment led to an increased lesion severity, indicating that gonadotropins may promote ovarian cancer progression. Point mutations in the Tp53 and Ki-Ras genes were detected that are also characteristic of human ovarian carcinomas. Additionally, an overexpression of estrogen and progesterone receptors was observed in preneoplastic and early neoplastic lesions, suggesting a role of these receptors in ovarian cancer development. These data indicate that this DMBA animal model gives rise to ovarian lesions that closely resemble human ovarian cancer and it is adequate for additional studies on the mechanisms of the disease and its clinical management.
卵巢癌动物模型对于理解该疾病的发病机制以及测试新的治疗策略至关重要。对大鼠卵巢癌发生模型进行了改进，以产生在发病机制上类似于人类卵巢癌的卵巢癌前病变和肿瘤性病变。将显著更低剂量（每侧卵巢2至5微克）的7,12 - 二甲基苯并(a)蒽（DMBA）应用于一侧卵巢，以最大程度地保留其结构完整性。DMBA诱导的诱变还与重复性促性腺激素刺激相结合，以诱导卵巢表面上皮细胞的多个活跃增殖周期。动物被分为单独使用不同剂量DMBA或随后给予激素的三个治疗组。将经DMBA处理的卵巢与对侧对照器官进行比较，发现在癌前病变和肿瘤形成的形态学不同阶段存在上皮细胞起源的病变。它们的组织病理学以及向其他器官的扩散途径与人类卵巢癌非常相似。激素联合治疗导致病变严重程度增加，表明促性腺激素可能促进卵巢癌进展。检测到Tp53和Ki - Ras基因中的点突变，这些突变也是人类卵巢癌的特征。此外，在癌前病变和早期肿瘤性病变中观察到雌激素和孕激素受体的过表达，表明这些受体在卵巢癌发展中起作用。这些数据表明，这种DMBA动物模型产生的卵巢病变与人类卵巢癌非常相似，适用于对该疾病机制及其临床管理的进一步研究。
