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Ovarian cancer-derived ascitic fluids induce a senescence-dependent pro-cancerogenic phenotype in normal peritoneal mesothelial cells

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Abstract

Purpose

After the seeding ovarian cancer cells into the peritoneal cavity, ascitic fluid creates a microenvironment in which these cells can survive and disseminate. The exact nature of the interactions between malignant ascitic fluids and peritoneal mesothelial cells (HPMCs) in ovarian cancer progression has so far remained elusive. Here we assessed whether malignant ascitic fluids may promote the senescence of HPMCs and, by doing so, enhance the acquisition of their pro-cancerogenic phenotype.

Methods

Primary omentum-derived HPMCs, ovarian cancer-derived cell lines (A2780, OVCAR-3, SKOV-3), malignant ascitic fluids and benign ascitic fluids from non-cancerous patients were used in this study. Ovarian cancer cell proliferation, as well as HPMC proliferation and senescence, were determined using flow cytometry and β-galactosidase assays, respectively. Ovarian cancer cell migration was quantified using a Transwell assay. The concentrations of soluble agents in ascitic fluids, conditioned media and cell lysates were measured using DuoSet® Immunoassay Development kits.

Results

We found that HPMCs, when exposed to malignant ascitic fluids, exhibited decreased proliferation and increased senescence rates. The malignant ascitic fluids were found to contain elevated levels of HGF, TGF-β1 and GRO-1, of which HGF and GRO-1 were able to induce senescence in HPMCs. We also found that HPMCs subjected to malignant ascitic fluids or exogenously added HGF and GRO-1 stimulated ovarian cancer cell progression, which was manifested by an increased production of HA (adhesion), uPA (proliferation), IL-8 and MCP-1 (migration).

Conclusion

Our results indicate that malignant ascitic fluids may contribute to ovarian cancer progression by accelerating the senescence of HPMCs.

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Acknowledgments

The study was supported by a grant from the National Science Centre, Poland (registration number 2014/15/B/NZ3/00421). We would like to thank Dr. Eryk Naumowicz from the General Surgery Ward, Centrum Medyczne HCP, Poznań, Poland for providing the omental tissue specimens.

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Authors and Affiliations

  1. Department of Hypertensiology, Angiology and Internal Medicine, Poznań University of Medical Sciences, Długa 1/2 Str, 61-848, Poznań, Poland

    Justyna Mikuła-Pietrasik, Paweł Uruski, Kinga Matuszkiewicz, Andrzej Tykarski & Krzysztof Książek

  2. Division of Gynecological Surgery, Poznań University of Medical Sciences, Polna 33 Str, 60-535, Poznań, Poland

    Sebastian Szubert, Rafał Moszyński, Dariusz Szpurek & Stefan Sajdak

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  1. Justyna Mikuła-Pietrasik
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Correspondence to Krzysztof Książek.

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Informed consent was obtained from all individual participants included in the study. The experiments were approved by an institutional ethics committee (consent numbers: 187/14 and 543/14).

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Mikuła-Pietrasik, J., Uruski, P., Matuszkiewicz, K. et al. Ovarian cancer-derived ascitic fluids induce a senescence-dependent pro-cancerogenic phenotype in normal peritoneal mesothelial cells. Cell Oncol. 39, 473–481 (2016). https://doi.org/10.1007/s13402-016-0289-1

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