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The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma

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Abstract

High grade serous ovarian tumors often metastasize transperitoneally, a process that begins when small tumor nodules de-adhere and are released into the fluid of the abdominal cavity where they float freely to reach new sites on the peritoneal wall. Podocalyxin, a small anti-adhesive sialomucin, has been shown to contribute to non-adhesive membrane domain formation in some epithelia and is overexpressed in a variety of cancers. We therefore assessed podocalyxin expression on a previously characterized tissue microarray and found that 87% (169/194) of high grade serous epithelial ovarian carcinomas were positive for podocalyxin. In addition, cell surface localization of podocalyxin was associated with a significant decrease in disease-free survival in these tumors. When podocalyxin was force-expressed in serous ovarian carcinoma-derived OVCAR-3 cells it was targeted to the cell surface and it decreased the adhesion of these cells to mesothelial monolayers, fibronectin and immobilized β1 integrin-binding antibodies. This decrease in adhesion was associated with a modest decrease in cell surface β1 integrin. In monolayer culture, podocalyxin was targeted to the free, apical domains of OVCAR-3 cells and it appeared to decrease β1 integrin levels on the attached basolateral domains of the same cells. Furthermore, in 3-dimensional basement membrane gel culture, the cells formed small, cohesive nodules and podocalyxin localized to membrane domains at the cell–basement membrane interface. Therefore, podocalyxin’s ability to facilitate the formation of non-adhesive membrane domains may contribute to the formation of free-floating high grade serous tumor nodules during the initial steps of transperitoneal metastasis.

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Acknowledgments

M.G. was the recipient University of British Columbia and Babicki family graduate scholarships. M.K. was an Eli Lilly Canada Oncology Fellow and KMM is a Michael Smith Foundation for Health Research Scholar. This work was funded by a grant from the Canadian Institutes of Health Research to C.D.R and K.M.M.

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Authors and Affiliations

  1. Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada

    Jane A. Cipollone, Marcia L. Graves, Tak Poon & Calvin D. Roskelley

  2. Department of Pathology, University of Calgary, Calgary, AB, Canada

    Martin Köbel

  3. Genetic Pathology Evaluation Center, Vancouver Hospital, Vancouver, BC, Canada

    Steve E. Kalloger & C. Blake Gilks

  4. The Biomedical Research Center, University of British Columbia, Vancouver, BC, Canada

    Kelly M. McNagny

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  1. Jane A. Cipollone
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  2. Marcia L. Graves
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Correspondence to Calvin D. Roskelley.

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Cipollone, J.A., Graves, M.L., Köbel, M. et al. The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma. Clin Exp Metastasis 29, 239–252 (2012). https://doi.org/10.1007/s10585-011-9446-0

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