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PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4

Journal of Molecular Medicine volume 97, pages 691–709 (2019)Cite this article

A Correction to this article was published on 20 July 2019

This article has been updated

Abstract

Ovarian cancer is the leading cause of death among all the gynecological cancers in the USA. Ovarian cancer employs a unique mode of metastasis, as exfoliated tumor cells disseminate within the peritoneal cavity, colonizing in several sites as well as accumulating ascites. Tumor recurrence and widespread metastasis are significant factors contributing to poor prognosis. PRSS21 is a metastasis-associated ovarian cancer gene that encodes the glycosyl-phosphatidylinositol-linked serine protease, testisin. Testisin expression is increased in multiple ovarian tumor types, with relatively little expression in normal tissues, but is differentially decreased in metastatic ovarian serous carcinomas compared to primary tumors. Here we explored the function of testisin in late-stage ovarian cancer progression using a murine xenograft model of ovarian intraperitoneal tumor metastasis. Increased tumor testisin expression inhibited intra-peritoneal tumor seeding and colonization, ascites accumulation, and metastatic tumor burden that was dependent on catalytically active testisin. The known testisin substrate, protease-activated receptor-2 (PAR-2), is a target of testisin activity. Gene profiling and mechanistic studies demonstrate that testisin activity suppresses the synthesis and secretion of pro-angiogenic angiopoietins, ANG2 and ANGPTL4, which normally promote vascular leak and edema. These observations support a model wherein testisin activates PAR-2 to antagonize proangiogenic angiopoietins that modulate vascular permeability and ascites accumulation associated with ovarian tumor metastasis.

Key messages

  • Testisin inhibits metastatic ovarian tumor burden and ascites production.

  • Testisin activity antagonizes ANG2 and ANGPTL4 synthesis and secretion.

  • PAR-2 is a proteolytic target of testisin on the surface of ovarian cancer cells.

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Change history

  • 20 July 2019

    The affiliation of Erik W. Martin is corrected in this paper.

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Acknowledgements

We thank Eun Yong Choi, M.D., and Rena Lapidus, Ph.D., of the Translational Laboratory Shared Services, University of Maryland School of Medicine, for assistance with the in vivo tumor studies and the in vivo bioluminescence imaging.

Funding

This work was supported by the National Institutes of Health Grants R01 CA196988, R01 HL118390 and T32 CA154274.

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Authors and Affiliations

  1. Center for Vascular and Inflammatory Diseases, Department of Physiology, and the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 800 West Baltimore Street Rm 220, Baltimore, MD, 21201, USA

    Gregory D. Conway, Marguerite S. Buzza, Erik W. Martin, Nadire Duru, Tierra A. Johnson, Raymond J. Peroutka, Nisha R. Pawar & Toni M. Antalis

  2. Laboratory of Molecular Biology and Immunology, National Institute on Aging, NIH, Baltimore, MD, USA

    Erik W. Martin

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  1. Gregory D. Conway
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  2. Marguerite S. Buzza
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  3. Erik W. Martin
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Correspondence to Toni M. Antalis.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Maryland School of Medicine Institutional Animal Care and Use Committee (IACUC), the institution at which the studies were conducted.

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Conway, G.D., Buzza, M.S., Martin, E.W. et al. PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4. J Mol Med 97, 691–709 (2019). https://doi.org/10.1007/s00109-019-01763-3

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Keywords

  • Testisin
  • Ovarian metastasis
  • ANG2
  • Ascites
  • Serine protease