Models of ovarian cancer metastasis: Murine models

Sale, Sanja; Oršulić, Sandra

doi:10.1016/j.ddmod.2006.05.006

Cited by 27 publications

(29 citation statements)

References 15 publications

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“…One method for identifying such molecules is through the study of model organisms. Several laboratories have developed mouse models of ovarian cancer through targeted disruption or expression of candidate ovarian cancer tumor suppressors and oncogenes in the proposed site of origin of ovarian cancer- the ovarian surface epithelium (OSE) (4). Although useful for the characterization of candidate molecules, the mammalian ovary does not lend itself to large-scale forward genetic screens that can identify new molecules.…”

Section: Introductionmentioning

confidence: 99%

Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene

et al. 2010

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The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer. Cancer Res; 70(21); 8517-25. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene

et al. 2010

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“…Tumor masses were calculated by caliper measurements using the formula “1/2a × b(Asghar et al, 2015)”, where “a” is the long diameter and “b” is the short diameter (in mm). For the metastasis model, 2 × 10 6 A2780 cells labeled with luciferase were injected intraperitoneally into nude mice, a model for which the gross pathology and pattern of dissemination of tumor nodules resemble human metastatic ovarian cancer (Naora and Montell, 2005, Sale and Orsulic, 2006). The establishment and growth of tumors were monitored by bioluminescent imaging with the Xenogen imaging system (IVIS) as described previously (Li et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer

Zhang

Liu

et al. 2016

EBioMedicine

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Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin-melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelial–mesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent.Research in contextArtemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin-melphalan conjugate, possesses marked in-vitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent.

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“…In particular, intraperitoneal or orthotopic xenografts are useful for modeling the advanced stages of ovarian carcinomas (3). These xenografts produce carcinomatosis in the peritoneal cavity, with large volumes of ascites resembling human ovarian metastatic phenotypes (4-6).…”

Section: Introductionmentioning

confidence: 99%

“…Ovarian cancer cells disseminate primarily in the peritoneal cavity and subsequently implant onto mesothelial surfaces (3). The biological process of metastasis is complex at the molecular level, involving adhesion, migration, invasion, growth, proliferation and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer

et al. 2014

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A lack of reliable biomarkers for the early detection and risk of metastatic recurrences makes ovarian cancer the most lethal gynecological cancer. To understand the molecular mechanisms involved in ovarian cancer metastasis in vivo, we analyzed the transcriptional expression pattern in metastatic implants of human ovarian carcinoma xenografts in mice. The expression of 937 genes was significantly different, by at least 2-fold, in the xenografts compared with that in SK-OV-3 cells. We investigated the mechanisms that regulate the expression of one of the profoundly upregulated genes, interferon-induced transmembrane protein 1 (IFITM1), in the metastatic implants. Specific CpG sites within the IFITM1 promoter were hypomethylated in the metastatic implants relative to those in the wild-type SK-OV-3 cells. Treating wild-type SK-OV-3 cells with the demethylating agent 5-aza-2'-deoxycytidine enhanced IFITM1 expression in a dose-dependent manner, implying transcriptional regulation by promoter methylation. We also found that IFITM1 overexpression caused increased migration and invasiveness in SK-OV-3 cells. Our results demonstrate that IFITM1 could be a novel metastasis-promoting gene that enhances the metastatic phenotype in ovarian cancer via epigenetic transcriptional regulation. Our findings also suggest that the status of DNA methylation within the IFITM1 promoter region could be a biomarker indicating metastatic progression in ovarian cancer.

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Models of ovarian cancer metastasis: Murine models

Cited by 27 publications

References 15 publications

Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene

Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene

Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer

Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer

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