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

Aditi Kothari,Matthew J Flick

doi:10.3390/ijms22105138

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.

Highlights

Loretta L. del Mercato and Pancreatic cancer develops from unrestricted and abnormal growth of cells in the tissues of the pancreas
Testing the therapeutic efficacy of targeting Alternatively spliced tissue factor (asTF) in Pancreatic ductal adenocarcinoma (PDAC), this study reports the use of asTF antibody to reduce PDAC tumor progression
Considering the role of asTF in PDAC spread in host cells, this study points to asTF as a potent target in PDAC

Summary

Introduction

Loretta L. del Mercato and Pancreatic cancer develops from unrestricted and abnormal growth of cells in the tissues of the pancreas. It is imperative to fill knowledge gaps related to early detection of premalignant conditions, comorbidities, mechanisms of pathogenesis, and pathways rendering pancreatic cancer refractive to therapy in order to improve surgical and medical management of this deadly disease. One study aimed to draw a correlation between global temporal patterns and socioeconomic development showed that around 55% of total incidences and 56% of mortality due to pancreatic cancer occurred in more developed areas in the world [6] It is more common in men as compared to women [5]. Neo-adjuvant therapy is given to patients with marginally resectable or early-stage tumor, in which case chemotherapy is provided before surgery [19]. The identification of pathways and mechanisms that render the PDAC microenvironment immune permissive and therapy sensitive offers a novel strategy for significantly enhancing current chemo- and immunotherapy strategies

Thrombosis in Cancer

Coagulation Activity as a Modifier of the PDAC Disease Progression

Protease-Activated Receptor-1 Signaling in Cancer Progression

Targeting PAR1 as a Therapeutic Approach in PDAC

Findings

Summary