title: The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma.
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.
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cipollone
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Graves
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Tak
authors.initials: T
authors.lastname: Poon
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McNagny
authors.forename: Calvin D
authors.initials: CD
authors.lastname: Roskelley
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018293:Cystadenoma, Serous / Q000473:pathology*; D004717:Endometrium / Q000737:chemistry; D005187:Fallopian Tubes / Q000737:chemistry; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000032:analysis; D010051:Ovarian Neoplasms / Q000473:pathology*; D010053:Ovary / Q000737:chemistry; D010534:Peritoneal Neoplasms / Q000556:secondary*; D012795:Sialoglycoproteins / Q000032:analysis / Q000502:physiology*
chemical_list: D019012:Integrin beta1; D012795:Sialoglycoproteins; C001643:podocalyxin