The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions

Davidson, Ben; Holth, Arild; Hellesylt, Ellen; Tan, Tuan Zea; Huang, Ruby Yun‐Ju; Tropé, Claes G.; Nesland, Jahn M.; Thiery, Jean Paul

doi:10.1016/j.humpath.2014.10.004

Cited by 55 publications

(43 citation statements)

References 35 publications

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“…Role of EMT in ovarian cancer malignancies is supported by the findings that mesenchymal-like gene expression signature is generally associated with aggressive and metastatic ovarian cancer (13, 14). It is also backed by the findings that factors inducing EMT often act as metastasis promoters (11).…”

Section: Discussionmentioning

confidence: 95%

“…Immunohistological analyses of both primary and metastatic ovarian carcinoma reveal that EMT is significantly associated with peritoneal metastasis and survival of ovarian cancer patients (13, 14). Correlation between EMT and aggressiveness of ovarian cancer is also supported by gene expression-based studies in which metastatic tumors generally exhibit mesenchymal signatures (15, 16).…”

Section: Introductionmentioning

confidence: 99%

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Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways

et al. 2016

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Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here, we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells while expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of MEK1/2 and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways

et al. 2016

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“…The most important hub-gene was the well-known tumor suppressor gene TP53 whose mutation (in 96% of HGSOC patients) is one of the first known molecular events in the development of HGSOC [18]. Further, several genes at central nodes in the sub-network have cell-cell and cell-matrix adhesion functions and were described in numerous human cancer entities: CTNNA1 [24, 25], NCAM1 [26, 27], and GFRA1 [28, 29]. MCM4 which was also at a central position in the network is essential for DNA replication and has already been described in other human cancer entities [30–32].…”

Section: Discussionmentioning

confidence: 99%

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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“…In one study, up-regulation of EMT-related transcription factors Snail, Slug, Twist2 and Zeb2 in gene level and Snail, Slug, Vimentin in protein level was found in cisplatin resistant EOC cell line A2780-cis compared with cisplatin sensitive EOC cell line A2780 using gene expression and proteomic analysis, respectively [23]. Using 100 fresh advanced-stage ovarian serous carcinoma effusions, Davidson et al analyzed 10 EMT and CSC protein markers including E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11 as well as Vimentin, and identified Vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions [24]. It was also found that reversal of EMT by down-regulating EMT makers can restore the chemosensitivity in OC.…”

Section: Emt In Ovarian Cancer Chemoresistancementioning

confidence: 99%

Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer

et al. 2016

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Chemoresistance is the main challenge for the recurrent ovarian cancer therapy and responsible for treatment failure and unfavorable clinical outcome. Understanding mechanisms of chemoresistance in ovarian cancer would help to predict disease progression, develop new therapies and personalize systemic therapy. In the last decade, accumulating evidence demonstrates that epithelial-mesenchymal transition and cancer stem cells play important roles in ovarian cancer chemoresistance and metastasis. Treatment of epithelial-mesenchymal transition and cancer stem cells holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. In this review, we focus on the role of epithelial-mesenchymal transition and cancer stem cells in ovarian cancer chemoresistance and explore the therapeutic implications for developing epithelial-mesenchymal transition and cancer stem cells associated therapies for future ovarian cancer treatment.

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The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions

Cited by 55 publications

References 35 publications

Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways

Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways

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

Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer

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