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.

Keywords: PDAC; antitumor immunity; protease-activated receptor; thrombin.

Figure 1

PAR1 signaling in cancer progression. PAR1 promotes tumor growth, angiogenesis, invasion, and metastasis through multiple molecular mechanisms.

Figure 2

PAR1 in PDAC; TF-Thrombin and MMPs are agonists of the cell surface receptor PAR1 that is expressed on the surface of PDAC tumor cells and stromal cells. PAR1 activity shapes multiple elements of the cancer cell and stromal cell repertoire as well as the desmoplastic matrix associated with PDAC.