Spontaneous Ovarian Tumors Research Articles

Ovarian Cancer Animal Models for Preclinical Studies and Development of Ovarian Cancer Drugs

Treatment for ovarian carcinoma is still far from optimal, animal models are still needed to study human epithelial ovarian cancer. Animal models of ovarian cancer are very important for understanding the pathogenesis of the disease and for testing new treatment strategies. Ovarian carcinogenesis models in mice have been modified and repaired to produce preneoplastic lesions and neoplastic ovaries that are pathogens resembling human ovarian cancer. Although spontaneous ovarian tumors in mice have been reported, some of the shortcomings of existing studies preclude their use as animal models of ovarian cancer. Because of this, many efforts have been made to develop animal models that are relevant for ovarian cancer. Experimental animal models are developed accurately to represent cellular and molecular changes associated with the initiation and development of human ovarian cancer. Accurate experimental models have significant potential in facilitating the development of better methods for early detection and treatment of ovarian cancer. Several animal models of ovarian cancer have been reported, including manipulation of various reproductive factors or exposure to carcinogens. The latest advance in ovarian cancer modeling is using genetically engineered mice.

Chemopreventive and Antitumor Efficacy of Curcumin in a Spontaneously Developing Hen Ovarian Cancer Model.

We investigated the effect of daily dietary curcumin intake on the development and progression of spontaneous ovarian cancer in a galline (hen) model, as the chicken is the only nonhuman animal in which ovarian cancer spontaneously develops with a high prevalence. At the end of 12 months, ovarian cancer had spontaneously developed in 39% (35/90) of control hens not fed curcumin (n = 90). In comparison, it spontaneously developed in 27% (24/90) and 17% (15/90) of hens given curcumin at 25.8 (n = 90) and 53.0 mg/day (n = 90), respectively (P = 0.004). This represented significant dose-dependent reductions in overall ovarian cancer incidence in the 25.8 and 53.0 mg/day curcumin-fed groups (31% and 57%, respectively). Daily curcumin intake also reduced ovarian tumor sizes (P = 0.04) and number of tumors (P = 0.006). Evaluation of the molecular mechanisms underlying the chemopreventive and antitumor effects of curcumin revealed that NF-κB and STAT3 signaling pathways were significantly inhibited but that the nuclear factor erythroid 2/heme oxygenase 1 antioxidant pathway was induced by curcumin intake in a dose-dependent manner in ovarian tissues (P < 0.05). Sequencing of the Ras family genes (KRAS, NRAS, and HRAS) revealed less frequent KRAS and HRAS mutations in ovarian tumors in the curcumin-fed animals. In conclusion, our results demonstrated for the first time that daily curcumin intake leads to a significant and dose-dependent reduction in spontaneous ovarian cancer incidence and tumor growth, indicating a tremendous role for curcumin as a chemopreventive strategy for ovarian cancer. Cancer Prev Res; 11(1); 59-67. ©2017 AACR.

Abstract TMEM-027: TARGETING RGNEF (P190RHOGEF/ARHGEF28) IMPAIRS OVARIAN TUMOR INITIATION AND PROGRESSION

Abstract Rho GTPase regulatory and integrin signaling pathways are associated with poor high-grade serous ovarian carcinoma (HGSOC) patient survival1. Focal adhesion kinase (FAK) transmits signals from integrins and promotes HGSOC tumor progression through mechanisms involving tumor-stromal cell interactions2. We previously found that the Rho guanine nucleotide exchange factor Rgnef (also named p190RhoGEF or Arhgef28) activates FAK as well as RhoA GTPase activity in mouse fibroblasts3. Here we find that Rgnef protein expression is elevated in Stage 3-4 HGSOC and that Rgnef knockout prevents spontaneous ovarian tumor formation in the MISIIR-T-antigen (TAg) induced C57BL/6 mouse model. At 17 weeks, Rgnef-/-;TAg ovarian tumors were significantly smaller (p&amp;lt;0.001) than Rgnef+/+;TAg controls. Primary Rgnef-/-;TAg and Rgnef+/+;TAg tumor cells were isolated and expanded ex vivo. Although loss of Rgnef did not alter growth as 3D spheroids, Rgnef-/-;TAg orthotopic (ovarian bursa) and intraperitoneal tumors were significantly smaller (p&amp;lt;0.01) than Rgnef+/+;TAg tumors in MISIIR-TAg-Low C57BL/6 syngeneic mice. Notably, FAK activation (as measured by FAK Y397 phosphorylation) was decreased in Rgnef-/-;TAg ascites-associated tumor cells. Together, these studies show that Rgnef loss impedes tumor growth independently of stromal Rgnef status and supports the notion that an Rgnef-FAK signaling linkage facilitates ovarian tumor initiation and progression. 1.Zhang, H., et al. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer. Cell 166 (2016). 2.Sulzmaier, F.J., Jean, C. &amp; Schlaepfer, D.D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer 14, 598-610 (2014). 3.Miller, N.L., et al. A non-canonical role for Rgnef in promoting integrin-stimulated focal adhesion kinase activation. J. Cell Sci. 126, 5074-5085 (2013). Citation Format: Elizabeth G. Kleinschmidt, Nichol L.G. Miller, Isabelle Tancioni, Denise C. Connolly, David D. Schlaepfer. TARGETING RGNEF (P190RHOGEF/ARHGEF28) IMPAIRS OVARIAN TUMOR INITIATION AND PROGRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-027.

VAT-associated ST2+Tregs from omentum support tolerance to peripheral tumors

Abstract Tumor metastasis to theomentum is associated with poor clinical outcomes. Although the omentum hasimmune function due to the activities of milky spots, the role of this organ inanti-tumor immunity has not been completely described. By implanting tumor cells in mice we found that peritoneal tumors are not rejected and cause an increasein visceral adipose tissue (VAT)-associated regulatory T cells in the omentumas well as low frequency of tumor specific CD8 T cells. Additionally, peritoneal tumors impaired the immunity to secondary dermal tumors by limiting the expansion of tumor specific CD8 T cells that mediate tumor rejection. To better understand this phenomenon, we studied the VAT-associated Tregs, which can be divided in ST2+ and ST2- (ST2 a component of the IL-33R). Particularly, VAT-associated ST2+ Tregs are not found in conventional lymphoid organs, nonetheless we find that following peritoneal tumor inoculation ST2+ Tregs are mobilized and home to secondary dermal tumors. To test whether the ST2+ Tregs were responsible for preventing secondary dermal tumors, we inoculate mice lacking ST2 (ST2−/−) with peritoneal tumors and challenged them with dermal tumors; interestingly, we found that secondary dermal tumors where rejected in ST2−/− mice whereas tumors in wild type mice continue to grow. Finally, to corroborate our findings we used a mouse strain that develops spontaneous ovarian tumors that metastasize to the omentum. By treating these mice with anti-ST2 we observed a reduction in tumor weight, decrease in ST2+Tregs and an increase in tumor specific CD8+ cells in omentum and ovaries. Together these data suggest that omental ST2+ Tregs have an important role promoting and maintaining tolerance in tumor metastasis.

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.

Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma. However, evidence to support a tumor-suppressive role for BAP1 in cancer remains contradictory. To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. We observed spontaneous malignant tumors in 54 of 93 Bap1-mutant mice (58%) versus 4 of 43 (9%) wild-type littermates. All three Bap1-mutant models exhibited a high incidence and similar spectrum of neoplasms, including ovarian sex cord stromal tumors, lung and mammary carcinomas, and spindle cell tumors. Notably, we also observed malignant mesotheliomas in two Bap1-mutant mice, but not in any wild-type animals. We further confirmed that the remaining wild-type Bap1 allele was lost in both spontaneous ovarian tumors and mesotheliomas, resulting in the loss of Bap1 expression. Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates. Collectively, these findings provide genetic evidence that Bap1 is a bona fide tumor suppressor gene and offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility. Cancer Res; 76(9); 2836-44. ©2016 AACR.

Tumor ovárico semejante a tumor de células epitelioides perivasculares (PEComa) en boga (Leporinus obtusidens)

Domitrovic, H.A.; González, A.O.; Flores Quintana, C.I.; Rosciani, S.A.; Hernández, D.R.: Tumor ovárico semejante a tumor de células epitelioides perivasculares (PEComa) en boga (Leporinus obtusidens). Rev. vet. 26: 1, 63-68, 2015.

VEGFR2-Targeted Ultrasound Imaging Agent Enhances the Detection of Ovarian Tumors at Early Stage in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

Tumor-associated neoangiogenesis (TAN) is an early event in ovarian cancer (OVCA) development. Increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) by TAN vessels presents a potential target for early detection by ultrasound imaging. The goal of this study was to examine the suitability of VEGFR2-targeted ultrasound contrast agents in detecting spontaneous OVCA in laying hens. Effects of VEGFR2-targeted contrast agents in enhancing the intensity of ultrasound imaging from spontaneous ovarian tumors in hens were examined in a cross-sectional study. Enhancement in the intensity of ultrasound imaging was determined before and after injection of VEGFR2-targeted contrast agents. All ultrasound images were digitally stored and analyzed off-line. Following scanning, ovarian tissues were collected and processed for histology and detection of VEGFR2-expressing microvessels. Enhancement in visualization of ovarian morphology was detected by gray-scale imaging following injection of VEGFR2-targeted contrast agents. Compared with pre-contrast, contrast imaging enhanced the intensities of ultrasound imaging significantly (p < 0.0001) irrespective of the pathological status of ovaries. In contrast to normal hens, the intensity of ultrasound imaging was significantly (p < 0.0001) higher in hens with early stage OVCA and increased further in hens with late stage OVCA. Higher intensities of ultrasound imaging in hens with OVCA were positively correlated with increased (p < 0.0001) frequencies of VEGFR2-expressing microvessels. The results of this study suggest that VEGFR2-targeted contrast agents enhance the visualization of spontaneous ovarian tumors in hens at early and late stages of OVCA. The laying hen may be a suitable model to test new imaging agents and develop targeted therapeutics.

Abstract 989: NEDD9 expression promotes epithelial ovarian cancer growth and dissemination

Abstract NEDD9 (Neural precursor cell Expressed, Developmentally Downregulated 9) is a scaffolding protein with roles in focal adhesion signaling, cell motility and regulation of centrosome function. NEDD9 has been reported as an important player in development and progression of several different solid tumors; however, its role in gynecologic cancers is poorly understood. In this study we investigated the role of NEDD9 in development and progression of epithelial ovarian cancer (EOC) using murine models. Three mouse strains were used: MISIIR-TAg mice that develop spontaneous ovarian carcinomas; MISIIR-TAg-Low mice that express the TAg transgene, but do not develop tumors; and Nedd9 null mice. To determine the effects of loss of Nedd9 on ovarian carcinoma development, MISIIR-TAg and Nedd9-/- mice were crossed and spontaneous ovarian tumor growth in MISIIR-TAg;Nedd9-/- and MISIIR-TAg;Nedd9+/+ mice was monitored and quantified by longitudinal magnetic resonance imaging (MRI). MISIIR-TAg-Nedd9-/- mice, compared to MISIIR-TAg-Nedd9+/+ mice, exhibited delayed tumor development and decreased tumor burden. Correspondingly, microarray analysis of tumors showed that several key oncogenic signaling pathways were upregulated in MISIIR-TAg-Nedd9+/+ mice compared to MISIIR-TAg-Nedd9-/- mice. Murine ovarian carcinoma (MOVCAR) cell lines were established from MISIIR-TAg-Nedd9-/- and MISIIR-TAg-Nedd9+/+ mice and essential tumorigenic features compared using in vitro assays. Interestingly, although these cells displayed no differences in adhesion or proliferation, Nedd9-/- MOVCAR cells were more aggressive than Nedd9+/+ cells in assays of migration and invasion. However, when grown as orthotopic allografts in permissive MISIIR-TAg-Low;Nedd9+/+ hosts, in vivo tumor growth was delayed and the number of metastatic tumor nodules was decreased in mice engrafted with Nedd9-/- cells compared to those injected with Nedd9+/+ cells. To study the potential role of Nedd9 in the tumor microenvironment, immune cell populations were compared in: 1) orthotopic allografts of Nedd9+/+ MOVCAR cells grown in MISIIR-TAg-Low;Nedd9-/- and MISIIR-TAg-Low;Nedd9+/+ hosts; or 2) spontaneous ovarian tumors in MISIIR-TAg-Nedd9-/- and MISIIR-TAg-Nedd9+/+ mice. In the allograft model, the number and total volume of metastatic tumor nodules was not significantly different in Nedd9-/- or Nedd9+/+ hosts; however, genotype-associated differences in tumor infiltrating NK-cell numbers were observed. Comparison of the spontaneous tumor models showed that the number of tumor infiltrating macrophages and NK-cells were decreased in MISIIR-TAg-Nedd9-/- mice. Collectively, these data suggest that Nedd9 promotes development and progression of EOC, through induction of oncogenic signaling and by pro-tumorigenic alterations of the immune cell microenvironment. Citation Format: Rashid Gabbasov, Laura E. Bickel, Shane W. O'Brien, Samuel Litwin, Sachiko Seo, Erica A. Golemis, Denise C. Connolly. NEDD9 expression promotes epithelial ovarian cancer growth and dissemination. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 989. doi:10.1158/1538-7445.AM2014-989

Towards an Animal Model of Ovarian Cancer: Cataloging Chicken Blood Proteins Using Combinatorial Peptide Ligand Libraries Coupled with Shotgun Proteomic Analysis for Translational Research

Epithelial ovarian cancer is the most deadly gynecological cancer around the world, with high morbidity in industrialized countries. Early diagnosis is key in reducing its morbidity rate. Yet, robust biomarkers, diagnostics, and animal models are still limited for ovarian cancer. This calls for broader omics and systems science oriented diagnostics strategies. In this vein, the domestic chicken has been used as an ovarian cancer animal model, owing to its high rate of developing spontaneous epithelial ovarian tumors. Chicken blood has thus been considered a surrogate reservoir from which cancer biomarkers can be identified. However, the presence of highly abundant proteins in chicken blood has compromised the applicability of proteomics tools to study chicken blood owing to a lack of immunodepletion methods. Here, we demonstrate that a combinatorial peptide ligand library (CPLL) can efficiently remove highly abundant proteins from chicken blood samples, consequently doubling the number of identified proteins. Using an integrated CPLL-1DGE-LC-MSMS workflow, we identified a catalog of 264 unique proteins. Functional analyses further suggested that most proteins were coagulation and complement factors, blood transport and binding proteins, immune- and defense-related proteins, proteases, protease inhibitors, cellular enzymes, or cell structure and adhesion proteins. Semiquantitative spectral counting analysis identified 10 potential biomarkers from the present chicken ovarian cancer model. Additionally, many human homologs of chicken blood proteins we have identified have been independently suggested as diagnostic biomarkers for ovarian cancer, further triangulating our novel observations reported here. In conclusion, the CPLL-assisted proteomic workflow using the chicken ovarian cancer model provides a feasible platform for translational research to identify ovarian cancer biomarkers and understand ovarian cancer biology. To the best of our knowledge, we report here the most comprehensive survey of the chicken blood proteome to date.

Control of spontaneous ovarian tumors by CD8+ T cells through NKG2D-targeted delivery of antigenic peptide

BackgroundThere is an urgent need to develop targeted therapies for the control of advanced stage ovarian cancer because it is the most deadly gynecologic cancer. Antigen-specific immunotherapy is a promising approach because of the potential of the immune system to specifically target tumors without the toxicity associated with traditional chemoradiation. However, one of the major limitations for antigen-specific cancer immunotherapy is the pre-existing immune tolerance against endogenous targeted tumor antigens that frequently evolves during carcinogenesis. Here, we described the creation of a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8+ T cell-mediated immune attack, thereby circumventing many aspects of immune tolerance. The tumor-homing module, NKG2D, specifically binds to NKG2D ligand that is commonly overexpressed in ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8+ T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment.ResultsWe show that this therapeutic chimeric protein specifically loaded antigenic epitope onto the surface of NKG2D ligand-expressing ovarian tumor cells, rendering ovarian tumors susceptible to antigen-specific CTL-mediated killing in vitro. Furthermore, we show that intraperitoneal administration of our therapeutic chimeric protein followed by adoptive transfer of antigen-specific CD8+ T cells generates potent antitumor effects and significant accumulation of antigen-specific CD8+ T cells in the tumor loci.ConclusionsOur findings have promise for bypassing immune tolerance to enhance cancer immunotherapy.

Network analysis identifies an HSP90-central hub susceptible in ovarian cancer.

Epithelial ovarian cancer (EOC) is usually detected at an advanced stage and is frequently lethal. Although many patients respond to initial surgery and standard chemotherapy consisting of a platinum-based agent and a taxane, most experience recurrence and eventually treatment-resistant disease. Although there have been numerous efforts to apply protein-targeted agents in EOC, these studies have so far documented little efficacy. Our goal was to identify broadly susceptible signaling proteins or pathways in EOC. As a new approach, we conducted data-mining meta-analyses integrating results from multiple siRNA screens to identify gene targets that showed significant inhibition of cell growth. On the basis of this meta-analysis, we established that many genes with such activity were clients of the protein chaperone HSP90. We therefore assessed ganetespib, a clinically promising second-generation small-molecule HSP90 inhibitor, for activity against EOC, both as a single agent and in combination with cytotoxic and targeted therapeutic agents. Ganetespib significantly reduced cell growth, induced cell-cycle arrest and apoptosis in vitro, inhibited growth of orthotopic xenografts and spontaneous ovarian tumors in transgenic mice in vivo, and inhibited expression and activation of numerous proteins linked to EOC progression. Importantly, paclitaxel significantly potentiated ganetespib activity in cultured cells and tumors. Moreover, combined treatment of cells with ganetespib and siRNAs or small molecules inhibiting genes identified in the meta-analysis in several cases resulted in enhanced activity. These results strongly support investigation of ganetespib, a single-targeted agent with effects on numerous proteins and pathways, in augmenting standard EOC therapies.

Immune Cells in the Normal Ovary and Spontaneous Ovarian Tumors in the Laying Hen (Gallus domesticus) Model of Human Ovarian Cancer

BackgroundSpontaneous ovarian cancer in chickens resembles human tumors both histologically and biochemically. The goal was to determine if there are differences in lymphocyte content between normal ovaries and ovarian tumors in chickens as a basis for further studies to understand the role of immunity in human ovarian cancer progression.MethodsHens were selected using grey scale and color Doppler ultrasound to determine if they had normal or tumor morphology. Cells were isolated from ovaries (n = 6 hens) and lymphocyte numbers were determined by flow cytometry using antibodies to avian CD4 and CD8 T and B (Bu1a) cells. Ovarian sections from another set of hens (n = 26) were assessed to verify tumor type and stage and to count CD4, CD8 and Bu1a immunostained cells by morphometric analysis.ResultsT and B cells were more numerous in ovarian tumors than in normal ovaries by flow cytometry and immunohistochemistry. There were less CD4+ cells than CD8+ and Bu1a+ cells in normal ovaries or ovarian tumors. CD8+ cells were the dominant T cell sub-type in both ovarian stroma and in ovarian follicles compared to CD4+ cells. Bu1a+ cells were consistently found in the stroma of normal ovaries and ovarian tumors but were not associated with follicles. The number of immune cells was highest in late stage serous tumors compared to endometrioid and mucinous tumors.ConclusionsThe results suggest that similar to human ovarian cancer there are comparatively more immune cells in chicken ovarian tumors than in normal ovaries, and the highest immune cell content occurs in serous tumors. Thus, this study establishes a foundation for further study of tumor immune responses in a spontaneous model of ovarian cancer which will facilitate studies of the role of immunity in early ovarian cancer progression and use of the hen in pre-clinical vaccine trials.

An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for &lt;em&gt;in vivo&lt;/em&gt; Tumor Imaging and Monitoring of Tumor Immune Responses

Background: Ovarian cancer is generally diagnosed at an advanced stage where the case/fatality ratio is high and thus remains the most lethal of all gynecologic malignancies among US women 1,2,3. Serous tumors are the most widespread forms of ovarian cancer and 4,5 the Tg-MISIIR-TAg transgenic represents the only mouse model that spontaneously develops this type of tumors. Tg-MISIIR-TAg mice express SV40 transforming region under control of the Mullerian Inhibitory Substance type II Receptor (MISIIR) gene promoter 6. Additional transgenic lines have been identified that express the SV40 TAg transgene, but do not develop ovarian tumors. Non-tumor prone mice exhibit typical lifespan for C57Bl/6 mice and are fertile. These mice can be used as syngeneic allograft recipients for tumor cells isolated from Tg-MISIIR-TAg-DR26 mice. Objective: Although tumor imaging is possible 7, early detection of deep tumors is challenging in small living animals. To enable preclinical studies in an immunologically intact animal model for serous ovarian cancer, we describe a syngeneic mouse model for this type of ovarian cancer that permits in vivo imaging, studies of the tumor microenvironment and tumor immune responses. Methods: We first derived a TAg+ mouse cancer cell line (MOV1) from a spontaneous ovarian tumor harvested in a 26 week-old DR26 Tg-MISIIR-TAg female. Then, we stably transduced MOV1 cells with TurboFP635 Lentivirus mammalian vector that encodes Katushka, a far-red mutant of the red fluorescent protein from sea anemone Entacmaea quadricolor with excitation/emission maxima at 588/635 nm 8,9,10. We orthotopically implanted MOV1Kat in the ovary 11,12,13,14 of non-tumor prone Tg-MISIIR-TAg female mice. Tumor progression was followed by in vivo optical imaging and tumor microenvironment was analyzed by immunohistochemistry. Results: Orthotopically implanted MOV1Kat cells developed serous ovarian tumors. MOV1Kat tumors could be visualized by in vivo imaging up to three weeks after implantation (fig. 1) and were infiltrated with leukocytes, as observed in human ovarian cancers 15 (fig. 2). Conclusions: We describe an orthotopic model of ovarian cancer suitable for in vivo imaging of early tumors due to the high pH-stability and photostability of Katushka in deep tissues. We propose the use of this novel syngeneic model of serous ovarian cancer for in vivo imaging studies and monitoring of tumor immune responses and immunotherapies.

An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for &lt;em&gt;in vivo&lt;/em&gt; Tumor Imaging and Monitoring of Tumor Immune Responses

Ovarian cancer is generally diagnosed at an advanced stage where the case/fatality ratio is high and thus remains the most lethal of all gynecologic malignancies among US women. Serous tumors are the most widespread forms of ovarian cancer and the Tg-MISIIR-TAg transgenic represents the only mouse model that spontaneously develops this type of tumors. Tg-MISIIR-TAg mice express SV40 transforming region under control of the Mullerian Inhibitory Substance type II Receptor (MISIIR) gene promoter. Additional transgenic lines have been identified that express the SV40 TAg transgene, but do not develop ovarian tumors. Non-tumor prone mice exhibit typical lifespan for C57Bl/6 mice and are fertile. These mice can be used as syngeneic allograft recipients for tumor cells isolated from Tg-MISIIR-TAg-DR26 mice. Although tumor imaging is possible, early detection of deep tumors is challenging in small living animals. To enable preclinical studies in an immunologically intact animal model for serous ovarian cancer, we describe a syngeneic mouse model for this type of ovarian cancer that permits in vivo imaging, studies of the tumor microenvironment and tumor immune responses. We first derived a TAg+ mouse cancer cell line (MOV1) from a spontaneous ovarian tumor harvested in a 26 week-old DR26 Tg-MISIIR-TAg female. Then, we stably transduced MOV1 cells with TurboFP635 Lentivirus mammalian vector that encodes Katushka, a far-red mutant of the red fluorescent protein from sea anemone Entacmaea quadricolor with excitation/emission maxima at 588/635 nm. We orthotopically implanted MOV1(Kat) in the ovary of non-tumor prone Tg-MISIIR-TAg female mice. Tumor progression was followed by in vivo optical imaging and tumor microenvironment was analyzed by immunohistochemistry. Orthotopically implanted MOV1(Kat) cells developed serous ovarian tumors. MOV1(Kat) tumors could be visualized by in vivo imaging up to three weeks after implantation (fig. 1) and were infiltrated with leukocytes, as observed in human ovarian cancers (fig. 2). We describe an orthotopic model of ovarian cancer suitable for in vivo imaging of early tumors due to the high pH-stability and photostability of Katushka in deep tissues. We propose the use of this novel syngeneic model of serous ovarian cancer for in vivo imaging studies and monitoring of tumor immune responses and immunotherapies.

Tumor and reproductive traits are linked by RNA metabolism genes in the mouse ovary: a transcriptome-phenotype association analysis

BackgroundThe link between reproductive life history and incidence of ovarian tumors is well known. Periods of reduced ovulations may confer protection against ovarian cancer. Using phenotypic data available for mouse, a possible association between the ovarian transcriptome, reproductive records and spontaneous ovarian tumor rates was investigated in four mouse inbred strains. NIA15k-DNA microarrays were employed to obtain expression profiles of BalbC, C57BL6, FVB and SWR adult ovaries.ResultsLinear regression analysis with multiple-test control (adjusted p ≤ 0.05) resulted in ovarian tumor frequency (OTF) and number of litters (NL) as the top-correlated among five tested phenotypes. Moreover, nearly one-hundred genes were coincident between these two traits and were decomposed in 76 OTF(–) NL(+) and 20 OTF(+) NL(–) genes, where the plus/minus signs indicate the direction of correlation. Enriched functional categories were RNA-binding/mRNA-processing and protein folding in the OTF(–) NL(+) and the OTF(+) NL(–) subsets, respectively. In contrast, no associations were detected between OTF and litter size (LS), the latter a measure of ovulation events in a single estrous cycle.ConclusionLiterature text-mining pointed to post-transcriptional control of ovarian processes including oocyte maturation, folliculogenesis and angiogenesis as possible causal relationships of observed tumor and reproductive phenotypes. We speculate that repetitive cycling instead of repetitive ovulations represent the actual link between ovarian tumorigenesis and reproductive records.

Spontaneous ovarian tumors in twelve baboons: a review of ovarian neoplasms in non-human primates.

Twelve spontaneous ovarian tumors were found in the Southwest Foundation for Biomedical Research baboon colony. These included four granulosa cell tumors, three teratomas, two endometrioid carcinomas, one seromucinous cystadenofibroma, a cystic papillary adenocarcinoma, and an ovarian carcinoma. Age was a pre-disposing factor. With one exception, the tumors of surface epithelial- and sex cordstromal origin occurred in baboons over 17 years of age. The exceptional animal was 7 years of age when a malignant granulosa cell tumor with Sertoli cell differentiation was identified. The two endometrioid tumors, which were found in 17- and 30-year-old animals, were both associated with endometriosis. In contrast, the teratomas, which are tumors of germ cell origin, were found in younger animals, i.e. 17 years of age or younger. One case of an ovarian carcinoma with metastases was observed in a 6-month-old infant. Cases of spontaneous ovarian tumors from the literature are reviewed.

Experimental Induction of Ovarian Sertoli Cell Tumors in Rats by N-Nitrosoureas

Spontaneous ovarian tumors are very rare in ACI, Wistar, F344 and Donryu rats; the few neoplasms found are of the granulosa/theca cell type. Ovarian tumors were also rare in these strains of rats when given high doses of N-alkyl-N-nitrosoureas continuously in the drinking water for their life-span; however, relatively high incidences of Sertoli cell tumors or Sertoli cell tumors mixed with granulosa cell tumors were induced in Donryu rats after administration of either a 400 ppm N-ethyl-N-nitrosourea solution in the drinking water for 4 weeks or as a single dose of 200 mg N-propyl-N-nitrosourea per kg body weight by stomach tube. Typical Sertoli cell tumors consisted of solid areas showing tubular formation. The tubules were lined by tall, columnar cells, with abundant, faintly eosinophilic, often vacuolated cytoplasm, and basally oriented, round nuclei, resembling seminiferous tubules in the testes. In some cases, Sertoli cell tumor elements were found mixed with areas of granulosa cells. The induction of ovarian Sertoli cell tumors in Donryu rats by low doses of nitrosoureas may provide a useful model for these tumors in man.

Ovarian Neoplasia in the Sprague-Dawley Rat

Macroscopic and microscopic characteristics of 210 spontaneous ovarian tumors from 7748 Sprague-Dawley rats are described. The tumors were classified as tubular adenoma, anaplastic adenocarcinoma, papillary cystadenoma, papillary cystadenocarcinoma, mesothelioma, sertoliform tubular adenoma, Sertoli's cell tumor, granulosa cell tumor, thecal cell tumor, polycystic sex cord/stromal tumor, and lipoid cell tumor. The histogenesis of the tumor types is discussed.

Ovarian neoplasia in the Sprague-Dawley rat.

Macroscopic and microscopic characteristics of 210 spontaneous ovarian tumors from 7748 Sprague-Dawley rats are described. The tumors were classified as tubular adenoma, anaplastic adenocarcinoma, papillary cystadenoma, papillary cystadenocarcinoma, mesothelioma, sertoliform tubular adenoma, Sertoli's cell tumor, granulosa cell tumor, thecal cell tumor, polycystic sex cord/stromal tumor, and lipoid cell tumor. The histogenesis of the tumor types is discussed.

Spontaneous Ovarian Tumors in Han:NMRI Mice: Histologic Classification, Incidence, and Influence of Food Restriction

In a life-span study with female Han:NMRI virgin mice (300 of a fat subline, 300 of a lean subline, and 300 controls), a total of 424 mice developed 673 ovarian tumors. Half of the mice in each group were fed ad libitum, and for the other half food was restricted. Most prevalent were tubular adenomas followed by granulosa and Sertoli cell tumors. Altogether, 42 neoplasms were classified as tubular adenocarcinomas, and 21, as luteomas . The general incidence of tumors increased sharply beyond the 18th month of age. Granulosa cell tumors arose relatively early, and tubular adenocarcinomas occurred very late in life. The occurrence of ovarian tumors depended mainly on life expectancy. All animals subjected to food restriction lived longer and developed more ovarian neoplasms than those fed ad libitum.