Characterization of a Carcinogenesis Rat Model of Ovarian Preneoplasia and Neoplasia

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 g 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.

MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells

“…Furthermore, we also observed that the basal levels of the p53 protein were also increased in the MAD2DC-agar cells (Figure 5a). It is possible that DMBA treatment may have caused mutations on the p53 gene as previously reported (Stewart et al, 2004) which leads to stabilization of this protein. However, sequencing analysis of the p53 gene showed no evidence of mutation, suggesting that the increased p53 expression is not the result of DMBA-induced mutation.…”

“…For example, der(1)t(1;16) was observed in over 87% of the MAD2DC-agar cells while this aberration was not detected in the MAD2DC cells (see white circles in Figure 2a). Since the carcinogenic effect of DMBA is believed to be through its mutagenic effect on the genome (Stewart et al, 2004), it is not a surprise to observe the increased chromosomal structural alterations in the MAD2DC-agar cells. Cell cycle analysis revealed a similar pattern between MAD2DC and MAD2DC-agar cells before and after exposure to nocodazole (Figure 3a) and suggested that the polyploidy MAD2DC-agar cells were also able to undergo cell division in the presence on microtubule disruption.…”

“…Role of p53 and MEK pathways in the MAD2DC-induced transformation Carcinogens such as DMBA promotes tumorigenesis through inactivation of tumor suppressor pathways such as the p53 pathway possibly through induction of gene mutations (Stewart et al, 2004). Although the HPV E6 oncogene is able to inactivate p53 through premature degradation of this protein (Kessis et al, 1993), a functional p53 pathway has been reported in certain HPV E6/E7-immortalized cell lines (Butz et al, 1995).…”

Simultaneous optical coherence tomography and laser induced fluorescence imaging in rat model of ovarian carcinogenesis

“…The direct application of DMBA to the ovary has been shown to result in selective development of ovarian malignancies in both rats and mice. 2,[6][7][8][9][10] The development of a post-menopausal animal model for ovarian cancer may prove useful in evaluating diagnostic tools to aid in differentiating benign and malignant ovarian pathology and provide better understanding of features characteristic of early cancers to improve their detection. Optical coherence tomography is an emerging, non-destructive imaging modality using near-infrared light to create cross-sectional images of tissue structure with near histological resolution (2-20 µm) with the advantage of up to 2 mm penetration depth compared to other optical technologies which may only have 100 micron or less penetration.…”

Efeitos morfológicos, histológicos e moleculares dos moduladores seletivos dos receptores de estrogênios tamoxifeno e raloxifeno na prevenção primária de tumores mamários quimicamente induzidos em ratas

“…O gene ras, quando alterado (oncogen ras), o que ocorre em cerca de 10% a 20% dos tumores de mama (Stewart et al, 2004;De Vita et al, 2004) Rogers et al (1998) e Russo et al (1990Russo et al ( , 2005a.…”