Abstract
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.
Highlights
To improve its usage and physiologic relevance to the human disease, the DMBA model of ovarian cancer was modified (a) by significantly decreasing the DMBA dose, thereby preserving maximally the integrity of the organ and (b) by incorporating multiple gonadotropin hormone treatments, introducing an additional risk factor associated with human ovarian cancer, known to induce hyperovulation and enhanced mitogenesis of the ovarian surface ep
To determine the sequence of histologic and molecular changes elicited by DMBA in the ovary, subgroups of animals were sacrificed at various time points, up to 12 months (Supplemental Table 1)
An apparent decrease in volume was evident in the DMBAtreated ovaries in arms 1 and 2
Summary
Most incorporated gene changes far are associated with advanced human ovarian cancer, and their role in early-stage disease is unknown. Most genetic models developed to date are unable to reproduce the histopathological diversity of human ovarian cancer and give rise to rapidly developing, advanced-stage disease at very young age. The direct implantation of chemical carcinogens, such as 7,12-dimethylbenz(a)anthracene (DMBA) in the rat ovary [22,23,24], leads to the induction of ovarian tumors at an incidence of ϳ37%. These include adenocarcinomas, as well as stroma and mesothelial tumors [22, 23, 25]. To improve its usage and physiologic relevance to the human disease, the DMBA model of ovarian cancer was modified (a) by significantly decreasing the DMBA dose, thereby preserving maximally the integrity of the organ and (b) by incorporating multiple gonadotropin hormone treatments, introducing an additional risk factor associated with human ovarian cancer, known to induce hyperovulation and enhanced mitogenesis of the ovarian surface ep-
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