Background: Epithelial ovarian cancer (EOC) is the leading cause of cancer death in women. Most commonly, EOC forms loosely attached outgrowths that transit through the peritoneal fluid and attach to new sites. This unusual route of dissemination is associated with tumor heterogeneity, development of resistant disease, and abdominal organ obstruction. The urokinase receptor uPAR has long been recognized to assist the directional movement of migrating cells and elicits a plethora of cellular responses, several of which are mediated through its association with coagulation Factor XII (FXII).

Aims: To investigate if the FXII-uPAR axis in host and EOC cells synergistically influences tumor biology.

Methods: We performed tissue microarray analysis (TMA) , ex vivo signaling assays, and in vivo studies in models of EOC using wild type (WT), F12^-/-, and uPAR (Plaur^-/-) deleted mice.  

Results: TMA of human EOC tumors showed that FXII and uPAR were co-expressed in all major histologic subtypes of EOC but not in normal ovarian epithelium (Fig 1A-B). In murine studies, ID8 EOC cells resulted in faster rates of tumor development and ascitic fluid accumulation in WT mice (13.4 ± 0.92 ml) relative to F12^-/- (0.37 ± 0.26 ml) and Plaur^-/- (0.5 ± 0.5 ml) mice (Fig 1C). Importantly, there was significantly higher tumor burden in WT mice compared to F12^-/- and Plaur^-/- mice (Fig 1D). Invariably, loss of host FXII resulted in tumors with significantly reduced vascularity, increased apoptotic rates and reduced epithelial-to-mesenchymal transition (EMT) (Fig 1E-H). These FXII-uPAR effects on EOC tumor behavior, were causally linked to the hepatic and hematopoietic FXII pools, respectively.

FXII promotes EOC growth and dissemination.

Conclusions: These data show that FXII-uPAR support pro-invasive EOC functions to promote tumor maintenance and progression. Targeting this interaction may prove to be an effective therapeutic strategy for persistent or recurrent EOC.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-factor-xii-upar-axis-drives-ovarian-cancer-maintenance-and-progression/