Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis

3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of Antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HS(AT)) is expressed in human tissues, but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here we show that HS(AT) is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HS(AT) is expressed by healthy ductal cells and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions (PanINs), but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HS(AT) synthesis, in PDAC cells eliminated HS(AT) expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HS(AT)-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor (TF) and Factor VIIa. Furthermore, plasma from PDAC patients showed accumulation of HS(AT) suggesting its potential as a marker of tumor formation. These findings suggest that HS(AT) exerts a tumor suppressing function through recruitment of AT and that the decrease in HS(AT) during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.