Unknown,Transcriptomics,Genomics,Proteomics

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Apoptosis enhancing drugs overcome innate platinum resistance in CA125 negative tumor initiating populations of high grade serous ovarian cancer

ABSTRACT: High grade serous ovarian cancers (HGSC) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSCs contain a CA125 negative population enriched for carboplatin resistant cancer initiating cells. Transcriptome analysis reveals up-regulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125 negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125 negative population. Birinapant sensitizes CA125 negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase-8 and restoration of apoptosis. This co-therapy significantly improved disease free survival in vivo compared to either therapy alone in tumor-bearing mice. These findings suggest that therapeutic strategies that target CA125 negative cells may be useful in the treatment of HGSC. mRNA profiles of CA125 positive and negative populations, generated by next generation sequencing of populations FACS isolated from 10 independent dissociated primary human high grade serous ovarian cancers, were compared.

ORGANISM(S): Homo sapiens

SUBMITTER: Sanaz Memarzadeh

PROVIDER: E-GEOD-70072 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histologic analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal appearing p53-positive epithelium that are similar to “p53 signatures” in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these noninvasive precursor lesions, we also identified invasive adenocarcinoma in the ovary of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and WT C57BL/6. One of these genes, Top2a, which encodes topoisomerase II-alpha, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and specifically elevated in mouse STICs, but not in surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade, and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumorigenesis, as well as for developing novel approaches for the prevention, diagnosis, and therapy of this disease. Keywords: transgenic mouse model, ovarian cancer, fallopian tube, intraepithelial carcinoma 6 mouse fallopian tubes (FT) were analyzed with experimental repeats; 3 wildtype C57BL6 mice (FT) and 3 transgenic mogp-TAg (FT), with one set of each at 7, 8 and 9 weeks of age.

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Apoptosis enhancing drugs overcome innate platinum resistance in CA125 negative tumor initiating populations of high grade serous ovarian cancer

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