Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C1855645 (
KPC
)
1,473
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
(
KRas
G12D
, TRP53
R172H
) 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-1
KO
) failed to generate sizable tumors, a phenotype completely rescued by restoration of
Par-1
expression. Expression profiling of
KPC
and
KPC
-Par-1
KO
cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly,
KPC
-Par-1
KO
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-1
KO
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:Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion. 3104 98
