Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a 5-year survival rate of less than 10% following diagnosis. The aggressive and invasive properties of pancreatic cancer tumors coupled with poor diagnostic options contribute to the high mortality rate since most patients present with late-stage disease. Accordingly, PDAC is linked to the highest rate of cancer-associated venous thromboembolic disease of all solid tumor malignancies. However, in addition to promoting clot formation, recent studies suggest that the coagulation system in PDAC mediates a reciprocal relationship, whereby coagulation proteases and receptors promote PDAC tumor progression and dissemination. Here, upregulation of tissue factor (TF) by tumor cells can drive local generation of the central coagulation protease thrombin that promotes cell signaling activity through protease-activated receptors (PARs) expressed by both tumor cells and multiple stromal cell subsets. Moreover, the TF-thrombin-PAR1 signaling axis appears to be a major mechanism of cancer progression in general and PDAC in particular. Here, we summarize the current literature regarding the role of PAR1 in PDAC and review possibilities for pharmacologically targeting PAR1 as a PDAC therapeutic approach.

Pancreatic Cancer and Venous Thromboembolism

“…The release of these micro-vesicles fosters clotting activation locally and systemically in a malignant state [ 45 ]. Pancreatic cancer is often associated with elevated plasma levels of fibrinogen, factor (F) VIII, and D-dimers along with reduced levels of protein C and antithrombin III [ 4 ]. In general, tumor cells release interleukin-1 (IL-1), vascular endothelial growth factor (VEGF), tumor necrosis factor α(TNF-α), and other signaling molecules to induce inflammation in addition to coagulation [ 46 ].…”

“…Indeed, higher levels of circulating TFPI were observed in patients with metastatic disease compared to patients with non-metastatic disease in the same study [ 79 ]. Furthermore, the abnormal coagulation parameters associated with PDAC have also brought to attention to the potential of using assorted coagulation parameters, in addition to US FDA approved serum cancer antigen CA19-9 marker, as a viable screening method for PDAC [ 4 ]. An elevated CA19-9 level was a significant risk factor for VTE and the occurrence of VTE was, overall, associated with poor prognosis in PDAC patients [ 80 ].…”

“…It is projected that, by 2030, it will become the second leading cause of cancer-related deaths [ 3 ]. Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers (PCs), with a 5-year survival rate of less than 10% following diagnosis [ 4 , 5 ]. PDAC has the worst prognosis of any malignancy [ 6 ].…”

“…PDAC has the worst prognosis of any malignancy [ 6 ]. Notably, PDAC is linked to the highest rate of cancer-associated thrombosis (CAT) of all solid tumor malignancies [ 4 , 5 ]. Approximately 7.4% of patients diagnosed with PDAC will experience a form of VTE within 1 year of diagnosis, compared to overall cancer patients who have a risk of 3.1% [ 7 ].…”

Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The “Circulating Wound” Model

“…Several studies described a role of PARs in cancer development, in particular in the setting of pancreatic cancer, where PAR-1 appears to be crucial for disease progression, for promoting an immunosuppressive microenvironment, and for conferring chemoresistance [ 47 , 48 , 49 , 50 , 51 ]. PAR-1 germline polymorphisms are linked to the prognosis of the tumour [ 52 ].…”