The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma
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.
KeywordsOvarian cancer Marker Adhesion Progression
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.
- 11.Hsu YH, Lin WL, Hou YT, Pu YS, Shun CT, Chen CL, Wu YY, Chen JY, Chen TH, Jou TS (2010) Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7. Am J Pathol 176(6):3050–3061PubMedCrossRefGoogle Scholar
- 13.Somasiri A, Nielsen JS, Makretsov N, McCoy ML, Prentice L, Gilks CB, Chia SK, Gelmon KA, Kershaw DB, Huntsman DG, McNagny KM, Roskelley CD (2004) Overexpression of the anti-adhesin podocalyxin is an independent predictor of breast cancer progression. Cancer Res 64(15):5068–5073PubMedCrossRefGoogle Scholar
- 27.Gilks CB, Ionescu DN, Kalloger SE, Köbel M, Irving J, Clarke B, Santos J, Le N, Moravan V, Swenerton K, Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency (2008) Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol 39(8):1239–1251PubMedCrossRefGoogle Scholar
- 28.Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S, Bowen NJ, Ionescu DN, Rajput A, Prentice LM, Miller D, Santos J, Swenerton K, Gilks CB, Huntsman D (2008) Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 5(12):e232PubMedCrossRefGoogle Scholar
- 48.Kobel M, Gradhand E, Zeng K, Schmitt WD, Kriese K, Lantzsch T, Wolters M, Dittmer J, Strauss HG, Thomssen C, Hauptmann S (2006) Ezrin promotes ovarian carcinoma cell invasion and its retained expression predicts poor prognosis in ovarian carcinoma. Int J Gynecol Pathol 25(2):121–130PubMedCrossRefGoogle Scholar
- 49.Tabrizi AD, Kalloger SE, Köbel M, Cipollone J, Roskelley CD, Mehl E, Gilks CB (2010) Primary ovarian mucinous carcinoma of intestinal type: significance of pattern of invasion and immunohistochemical expression profile in a series of 31 cases. Int J Gynecol Pathol 29(2):99–107PubMedCrossRefGoogle Scholar