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Cancer Res. 2019 Jul 1;79(13):3417-3430. doi: 10.1158/0008-5472.CAN-18-3206. Epub 2019 May 2.

Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion.

Author information

1
Department of Biological Science and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana.
2
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio.
3
Ionis Pharmaceuticals, Inc., Antisense Drug Discovery, Carlsbad, California.
4
Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana.
5
Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, Ohio.
6
Department of Biological Science and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana. matthew.flick@cchmc.org sfk@purdue.edu.
7
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio. matthew.flick@cchmc.org sfk@purdue.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated and characterized C57Bl/6-derived KPC (KRasG12D, TRP53R172H ) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies, tumor growth and metastatic potential were significantly diminished by depletion of TF or Par-1 in cancer cells or by genetic or pharmacologic reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1-deleted KPC cells (KPC-Par-1KO) failed to generate sizable tumors, a phenotype completely rescued by restoration of Par-1 expression. Expression profiling of KPC and KPC-Par-1KO cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly, KPC-Par-1KO cells failed to form tumors in immune-competent mice but displayed robust tumor growth comparable to that observed with control KPC cells in immune-compromised NSG mice. Immune cell depletion studies indicated that CD8 T cells, but not CD4 cells or natural killer cells, mediated elimination of KPC-Par-1KO tumor cells in C57Bl/6 mice. These results demonstrate that PDAC is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor cell-derived PAR-1 and further indicate that one key mechanism of thrombin/PAR-1-mediated tumor growth is suppression of antitumor immunity in the tumor microenvironment. SIGNIFICANCE: The tissue factor-thrombin-PAR-1 signaling axis in tumor cells promotes PDAC growth and disease progression with one key mechanism being suppression of antitumor immunity in the microenvironment.

PMID:
31048498
PMCID:
PMC6699516
[Available on 2020-01-01]
DOI:
10.1158/0008-5472.CAN-18-3206

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