Malignant ascites determine the transmesothelial invasion of ovarian cancer cells

Mikuła-Pietrasik, Justyna; Uruski, Paweł; Szubert, Sebastian; Szpurek, Dariusz; Sajdak, Stefan; Tykarski, Andrzej; Książek, Krzysztof

doi:10.1016/j.biocel.2017.09.002

Cited by 33 publications

(31 citation statements)

References 23 publications

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“…Over the next few years, a plethora of data has accumulated that various types of intercellular junctions are important for the invasion of cancer cells 18 . To verify whether this relatively old observation could explain our current findings, we examined the expression of four arbitrarily selected junctional proteins that are constitutively expressed by PMCs, connexin 43 19 , E-cadherin 20 , occludin 21 , and desmoglein 22 . The proteins were analyzed in either samples of tumors, tumor-free zones of the peritoneum, or cultured PMCs.…”

Section: Resultsmentioning

confidence: 84%

Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells

Pakuła

Witucka

Uruski

et al. 2019

Sci Rep

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Mechanisms of transmesothelial invasion of ovarian cancer are still poorly understood. Here we examined whether this phenomenon may be determined by an expression of intercellular junctions in peritoneal mesothelial cells (PMCs). Analysis of ovarian tumors showed that cancer cells are localized below an intact layer of PMCs. The PMCs located near the invaded cancer cells displayed low expression of connexin 43, E-cadherin, occludin, and desmoglein, as well as expressed SA-β-Gal, a marker of senescence. Experiments in vitro showed that senescent PMCs exhibited decreased levels of the four tested intercellular junctions, and that the invasion of ovarian cancer cells through the PMCs increased proportionally to the admixture of senescent cells. Intervention studies showed that the expression of connexin 43, E-cadherin, occludin, and desmoglein in senescent PMCs could be restored upon the blockade of p38 MAPK, NF-κB, AKT, JNK, HGF, and TGF-β1. When these molecules were neutralized, the efficiency of the transmesothelial cancer cell invasion was diminished. Collectively, our findings show that the integrity of the peritoneal mesothelium, which is determined by the expression of junctional proteins, is critical for the invasion of ovarian cancer. They also indicate a mechanism by which senescent PMCs may promote the invasive potential of cancer cells.

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Section: Resultsmentioning

confidence: 84%

Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells

Pakuła

Witucka

Uruski

et al. 2019

Sci Rep

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“…An initiated EMT may explain the increased effectiveness of the transmesothelial invasion of ovarian cancer cells and may be considered as an additional pathomechanism of this process, next to that associated with the decreased expression of junctional proteins in the peritoneal mesothelium [7]. Recently, a similar shift toward the mesenchymal ovarian cancer cell phenotype after their exposure to the malignant ascites was reported as favoring their proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we discovered that malignant ascites modulate the efficacy of the transmesothelial invasion of ovarian cancer cells. This effect was linked to their ability to decrease the expression of several junctional proteins (connexin 43, E-cadherin, occludin, and desmoglein) in peritoneal mesothelial cells (PMCs), in a p38 MAPK- and NF-κB-dependent manner [7]. Increased invasive properties of ovarian cancer cells exposed to the ascites were also revealed by other authors, who additionally showed that the fluid may induce the formation of cellular spheroids [8].…”

Section: Introductionmentioning

confidence: 98%

The Epithelial-Mesenchymal Transition Initiated by Malignant Ascites Underlies the Transmesothelial Invasion of Ovarian Cancer Cells

Pakuła

Mikuła-Pietrasik

Witucka

et al. 2019

IJMS

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The role of the epithelial-mesenchymal transition (EMT) in ovarian cancer cell progression is unquestioned. In this report, we describe that malignant ascites, fluid that accumulates in the peritoneal cavity in a large group of patients with ovarian cancer, stimulate EMT in two representative ovarian cancer cell lines (A2780, SKOV-3). In addition, we identify the ascites-derived mediators of EMT and signaling pathways initiated in the cancer cells that underlie this phenomenon. Finally, we demonstrate that EMT induced in the cancer cells in response to the malignant ascites contributes to their increased transmesothelial invasion. Altogether, our study provides new insight into the mechanistic aspects of the malignant ascites-dependent exacerbation of the intraperitoneal progression of ovarian cancer.

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“…Ascites is common in women with advanced OC [ 19 ], and the ascites fluid is rich in proangiogenic factors including VEGF and immunosuppressive cells [ 20 , 21 ]. The concentration of proangiogenic factors in ascites is a marker of OC tumor invasiveness and a prognostic indicator of worse outcome in OC [ 20 , 22 , 23 ].…”

Section: Importance Of Tumoral Angiogenesis In Ovarian Cancermentioning

confidence: 99%

Are antiangiogenics a good ‘partner’ for immunotherapy in ovarian cancer?

et al. 2020

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Ovarian cancer (OC) is associated with poor survival because there are a limited number of effective therapies. Two processes key to OC progression, angiogenesis and immune evasion, act synergistically to promote tumor progression. Tumor-associated angiogenesis promotes immune evasion, and tumor-related immune responses in the peritoneal cavity and tumor microenvironment (TME) affect neovascular formation. Therefore, suppressing the angiogenic pathways could facilitate the arrival of immune effector cells and reduce the presence of myeloid cells involved in immune suppression. To date, clinical studies have shown significant benefits with antiangiogenic therapy as first-line therapy in OC, as well as in recurrent disease, and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab is now an established therapy. Clinical data with immunomodulators in OC are more limited, but suggest that they could benefit some patients with recurrent disease. The preliminary results of two phase III trials have shown that the addition of immunomodulators to chemotherapy does not improve progression-free survival. For this reason, it could be interesting to look for synergistic effects between immunomodulators and other active drugs in OC. Since bevacizumab is approved for use in OC, and is tolerable when used in combination with immunotherapy in other indications, a number of clinical studies are underway to investigate the use of bevacizumab in combination with immunotherapeutic agents in OC. This strategy seeks to normalize the TME via the anti-VEGF actions of bevacizumab, while simultaneously stimulating the immune response via the immunotherapy. Results of these studies are awaited with interest.

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Malignant ascites determine the transmesothelial invasion of ovarian cancer cells

Cited by 33 publications

References 23 publications

Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells

Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells

The Epithelial-Mesenchymal Transition Initiated by Malignant Ascites Underlies the Transmesothelial Invasion of Ovarian Cancer Cells

Are antiangiogenics a good ‘partner’ for immunotherapy in ovarian cancer?

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