Peritoneal tumor spread in serous ovarian cancer-epithelial mesenchymal status and outcome

Auer, Katharina; Bachmayr-Heyda, Anna; Aust, Stefanie; Sukhbaatar, Nyamdelger; Reiner, Agnes T.; Grimm, Christoph; Horvat, Reinhard; Zeillinger, Robert; Pils, Dietmar

doi:10.18632/oncotarget.3746

Cited by 42 publications

(90 citation statements)

References 39 publications

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“…Specifically, 10/22 genes were differently expressed, namely BAG1, BIRC5, CCNB1, CLDN4 and 6, MMP9 and 11, MUC1, MYBL2, and SERPINB3. This finding of a gene signature for ascites-producing PC is consistent with previous data analyzing differences in gene expression between PC with miliary and non-miliary peritoneal spread [33]. In this study, Auer et al analyzed tumor tissues and ascites from 23 chemotherapy-naive patients by RNA-sequencing and flow cytometry.…”

Section: Discussionsupporting

confidence: 91%

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

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Tannapfel

et al. 2016

Geburtshilfe Frauenheilkd

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Background: Intraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel. Methods: Total RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes. Results: Gene expression profiles differed significantly between peritoneal cancer and non-peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival. Conclusions: In summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations.

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Section: Discussionsupporting

confidence: 91%

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

Rezniczek

Jüngst

Tannapfel

et al. 2016

Geburtshilfe Frauenheilkd

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“…2.54 for miliary (Table 2C), with the HR obtained in the training cohort with the 272 gene spread predictor [11] (HR = 1.74, CI 95 1.06–2.86, Table 2A). Again, the validation HR was within the CI 95 of the HR in the training cohort, indicating a successful validation.…”

Section: Resultsmentioning

confidence: 96%

“…It did not correlate with any of the clinicopathological parameters (age, FIGO stage, grade, and residual tumor). As we have already reported an independent negative prognostic impact on OS of the miliary spread type (predicted with a 272 gene spread predictor ) in our previous study [11], we applied this multiple Cox regression model to the validation cohort (Table 2A) replacing the 272 gene spread predictor with the 13 sRNA spread predictor . The risk for each patient from the validation cohort was calculated using the Cox regression model from the training cohort with the 13 sRNA spread predictor value.…”

Section: Resultsmentioning

confidence: 99%

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Small RNAs and the competing endogenous RNA network in high grade serous ovarian cancer tumor spread

et al. 2016

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High grade serous ovarian cancer (HGSOC) is among the most deadly malignancies in women, frequently involving peritoneal tumor spread. Understanding molecular mechanisms of peritoneal metastasis is essential to develop urgently needed targeted therapies. We described two peritoneal tumor spread types in HGSOC apparent during surgery: miliary (numerous millet-sized implants) and non-miliary (few big, bulky implants). The former one is defined by a more epithelial-like tumor cell characteristic with less immune cell reactivity and with significant worse prognosis, even if corrected for typical clinicopathologic factors.23 HGSOC patients were enrolled in this study. Isolated tumor cells from fresh tumor tissues of ovarian and peritoneal origin and from ascites were used for ribosomal RNA depleted RNA and small RNA sequencing. RT-qPCR was used to validate results and an independent cohort of 32 patients to validate the impact on survival. Large and small RNA sequencing data were integrated and a new gene-miRNA set analysis method was developed.Thousands of new small RNAs (miRNAs and piwi-interacting RNAs) were predicted and a 13 small RNA signature was developed to predict spread type from formalin-fixed paraffin-embedded tissues. Furthermore, integrative analyses of RNA sequencing and small RNA sequencing data revealed a global upregulation of the competing endogenous RNA network in tumor tissues of non-miliary compared to miliary spread, i.e. higher expression of circular RNAs and long non-coding RNAs compared to coding RNAs but unchanged abundance of small RNAs. This global deregulated expression pattern could be co-responsible for the spread characteristic, miliary or non-miliary, in ovarian cancer.

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“…Research has shown that opposing levels of E-Cadherin and vimentin occur in cells that have undergone EMT [60, 61]. Therefore, this new cell line may be an interesting model to study EOC processes related to peritoneal metastasis and invasion, because there is evidence that EMT transition might be involved in this tumor spread [62]. All the other five cell lines showed patterns of epithelial origin as suggested by the presence of cytokeratins and/or E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

et al. 2015

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Few cell line models of epithelial ovarian cancer (EOC) have been developed for the high-grade serous (HGS) subtype, which is the most common and lethal form of gynaecological cancer. Here we describe the establishment of six new EOC cell lines spontaneously derived from HGS tumors (TOV2978G, TOV3041G and TOV3291G) or ascites (OV866(2), OV4453 and OV4485). Exome sequencing revealed somatic TP53 mutations in five of the cell lines. One cell line has a novel BRCA1 splice-site mutation, and another, a recurrent BRCA2 nonsense mutation, both of germline origin. The novel BRCA1 mutation induced abnormal splicing, mRNA instability, resulting in the absence of BRCA1 protein. None of the cell lines harbor mutations in KRAS or BRAF, which are characteristic of other EOC subtypes. SNP arrays showed that all of the cell lines exhibited structural chromosomal abnormalities, copy number alterations and regions of loss of heterozygosity, consistent with those described for HGS. Four cell lines were able to produce 3D-spheroids, two exhibited anchorage-independent growth, and three (including the BRCA1 and BRCA2 mutated cell lines) formed tumors in SCID mice. These novel HGS EOC cell lines and their detailed characterization provide new research tools for investigating the most common and lethal form of EOC.

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Peritoneal tumor spread in serous ovarian cancer-epithelial mesenchymal status and outcome

Cited by 42 publications

References 39 publications

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

Small RNAs and the competing endogenous RNA network in high grade serous ovarian cancer tumor spread

Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

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