Mouse Ovarian Cancer Cell Line Research Articles

Src tyrosine kinase promotes survival and resistance to chemotherapeutics in a mouse ovarian cancer cell line

The vast majority of ovarian cancers originate in the ovarian surface epithelium. Unfortunately, there is a lack of appropriate animal models for ovarian cancer research. Spontaneously transformed mouse ovarian surface epithelial cells may provide a faithful animal model for human ovarian cancer. One such cell line (ID8) has been partially characterized. ID8 cells demonstrate constitutive Src tyrosine kinase activation with resulting phosphatidylinositol-3-kinase activation and Akt and forkhead phosphorylation. In addition, focal adhesion kinase is constitutively phosphorylated at tyrosine 925, a Src phosphorylation site, resulting in increased Ras activation. These features are common to human ovarian cancer cell lines. Inhibition of Src enhances the cell killing effects of both paclitaxel and cisplatinum. Finally, Src inhibition restores sensitivity of a drug resistant ID8 cell line. The ID8 mouse ovarian cancer cell line presents new opportunities to study ovarian cancer progression and pre-therapeutic trials in an immune competent background.

Estradiol enhances and estriol inhibits the expression of CYP1A1 induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin in a mouse ovarian cancer cell line

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is a ubiquitous pollutant and promoter of carcinogenesis. This study investigated the interaction between TCDD and different estrogens in a cancer cell line (ID8) derived from mouse ovarian epithelium. TCDD-induced ethoxyresorufin- O-deethylase (EROD) activity and cytochrome P4501A1 (CYP1A1) expression in a dose- and time-dependent manner. Estrogen receptor (ER) α mRNAs were constitutively expressed, but ERβ and progesterone receptor (PR) mRNAs were not expressed. Induction of EROD by TCDD was completely inhibited by a α-naphthoflavone and phenanthroline, two aryl hydrocarbon receptor (AhR) antagonists. Progesterone and gonadotropins (FSH and LH) had no effect on the induction of EROD by TCDD. Congeners of 17β-estradiol (E2) increased the induction of EROD activity by TCDD dose-dependently in the relative potency order: estrone (El)>E2⩾4-hydroxyestradiol (4OHE2)⩾2-hydroxyestradiol (2OHE2). In contrast, estriol (E3) decreased EROD activity induced by TCDD. E2 increased TCDD-induced CYP1A1 protein and mRNA whereas E3 decreased both the protein and mRNA. E2 did not alter luciferase activity induced by TCDD in cells transfected with a luciferase reporter containing dioxin response elements (DRE) or a CYP1A1 promoter. In contrast, E3 dose-dependently decreased the luciferase activity. A pure anti-estrogen (ICI 182 780) inhibited the interaction between E2 and TCDD but did not block E3's effect on EROD activity. These results indicate that E2 may affect TCDD-induced CYP1A1 expression by a mechanism different from E3 in ID8 cells. It appears that the potentiation of E2 in the induction of CYP1A1 by TCDD occurs by a mechanism involving ERα since a specific ER antagonist blocked the potentiation. The inhibitory effect of E3 may be due to a rapid direct effect on EROD and a later suppression of CYP1A1 expression.

Dominant-negative activity of a Brca1 truncation mutant: Effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line

In order to generate an in vitro mouse model for the study of human ovarian cancers, we compared the effects of a truncated Brca1 mutant expression on cellular phenotype with those of a full-length sense and antisense Brca1 expression in the ID-8 mouse epithelial ovarian cancer cell line. The examined cellular processes include proliferation, tumorigenicity in syngeneic mice in vivo and sensitivity/resistance to several cytotoxic drugs. We found that the expression of a spontaneous truncated Brca1 mutant in ID-8 cells which contain two endogenous wild-type Brca1 alleles led to a dominant-negative effect of Brca1, demonstrated by an increase in tumorigenicity in vivo and in chemosensitivity. Expression of a truncated Brca1 mutant in a mouse epithelial ovarian cancer cell line could thus provide a powerful in vitro model for the study of human BRCA1-related ovarian tumorigenesis.

Molecular pathways involved in response to ionizing radiation of ID-8 mouse ovarian cancer cells expressing exogenous full-length Brca1 or truncated Brca1 mutant.

BRCA1 germline mutations have been linked to the development of hereditary breast and ovarian cancers. Recent studies suggest that BRCA1 may function in the regulation of basic cellular processes, including gene transcription, and sensing and/or repair of DNA damage. To further delineate the BRCA1 upstream and downstream steps involved in its role in the cellular response to ionizing radiation, we compared the effects of expression of an exogenous full-length Brca1 with those of a truncated Brca1 mutant in the ID-8 mouse ovarian cancer cell line after irradiation. We found that expression of both full-length and truncated Brca1 increased resistance to ionizing radiation. Expression of truncated, but not full-length, Brca1 then allowed us to identify new potential downstream targets of mutated BRCA1 like MAPK/ERK pathway members and also key genes involved in mutated BRCA1 signaling pathway response to ionizing radiation such as p53 and p21WAF1/CIP1. We therefore established an in vitro mouse model for studying the molecular effects of human BRCA1 germline mutations.

Co-transduction of herpes simplex virus thymidine kinase gene and human interleukin-2 gene into mouse ovarian cancer cell line, OVHM.

We studied the thymidine kinase (TK) gene and the interleukin (IL)-2 gene co-transduction into tumor cells for a possible strategy of cancer gene therapy. A murine ovarian cancer cell line, OVHM, was retrovirally transduced with the TK (OVHM/TK) or the IL-2 gene (OVHM/IL-2). The TK or IL-2 expression was permanent in OVHM/TK or OVHM/IL-2. OVHM/TK cells were susceptible to gancyclovir (GCV) in vitro, and their intraperitoneal growth was completely regulated with GCV administration. The bystander effect was not observed in vitro and in vivo in this model, and only the marginal emergence of immune involvement was observed in the OVHM/TK-cured mice with GCV. OVHM/IL-2 cells produced IL-2 biologically active to be immunogenic, but still tumorigenic to kill the mice when inoculated intraperitoneally. Then, OVHM/TK cells were co-transduced with the IL-2 gene to establish OVHM/TK/IL-2 cells. OVHM/TK/IL-2 cells were also susceptible to GCV and transiently produced active IL-2. A significant resistance against the challenge of parental tumor cells was observed in the mice that were inoculated with OVHM/TK/IL-2 cells and cured with GCV administration. It is suggested that tumor cells transduced with both TK and IL-2 genes could be regressed with GCV administration with subsequent generation of immune activation in the host. Since the bystander effect may not always be a common phenomenon in gene therapy using the TK gene, this type of combination may be advantageous in the clinical application of gene therapy for human cancers.