Protease-activated receptor 2 suppresses lymphangiogenesis and subsequent lymph node metastasis in a murine pancreatic cancer model
Protease‐activated receptor‐2 (PAR‐2) is a G protein‐coupled receptor that functions as a cell‐surface sensor for coagulation factors and other proteases associated with the tumour microenvironment. Pancreatic cancer cells express high levels of PAR‐2 and activation of PAR‐2 may induce their prolife...
Saved in:
Published in | The Journal of pathology Vol. 234; no. 3; pp. 398 - 409 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Chichester, UK
John Wiley & Sons, Ltd
01.11.2014
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Protease‐activated receptor‐2 (PAR‐2) is a G protein‐coupled receptor that functions as a cell‐surface sensor for coagulation factors and other proteases associated with the tumour microenvironment. Pancreatic cancer cells express high levels of PAR‐2 and activation of PAR‐2 may induce their proliferation and migration. Interestingly, however, PAR‐2 expression is increased in stroma‐rich pancreatic cancer regions, suggesting a potential role of PAR‐2 in the tumour microenvironment. Here, we assessed the importance of PAR‐2 in the stromal compartment by utilizing an orthotopic pancreatic cancer model, in which tumour cells are PAR‐2‐positive, whereas stromal cells are PAR‐2‐negative. We assessed tumour weight and volume and analysed proliferation and (lymph)angiogenesis both in vivo and in vitro. We show that genetic ablation of PAR‐2 from the stromal compartment inhibits primary tumour growth, which is accompanied by reduced vascularization in primary tumours and reduced in tube formation of vascular endothelial cells in vitro. In contrast to smaller primary tumours, the number of lymph node metastases was increased in PAR‐2‐deficient animals, which was accompanied by an increased number of lymphatic vessels. In vitro tube‐formation assays show that PAR‐2 does not inhibit the intrinsic tube‐forming capacity of lymphatic endothelial cells, but that PAR‐2 actually inhibits cancer cell‐induced tube formation. Overall, stromal PAR‐2 thus plays a dual role in pancreatic cancer development by potentiating primary tumour growth but limiting lymphangiogenesis and subsequent lymph node metastasis. Our data identify a novel role of PAR‐2 in the tumour microenvironment and pinpoint PAR‐2 as a negative regulator of lymphangiogenesis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
---|---|
Bibliography: | ark:/67375/WNG-N9KX3V5V-R Figure S1. Validation of PAR-2 agonist peptides. Control transfected HEK cells (A) or PAR-2-transfected HEK cells (B) were stimulated with hPAR-2-AP (100 µm), after which Erk1/2 phosphorylation was assessed. (C, D) Erk1/2 phosphorylation of murine Swiss3T3 cells stimulated with hPAR-AP (C) or mPAR-2-AP; α-tubulin served as the loading control.Figure S2. Representative pictures of human pancreatic cancer slides stained for CD31 (A, brown) and D2-40 (B, brown). Paraffin sections obtained from patients with resectable pancreatic cancer were stained for CD31 (A, brown) and D2-40 (B, brown). Three different biopsies from three different patients were randomly selected from the tissue array. ArticleID:PATH4411 istex:C3B5AA597959DD2655E2B7C152F903D1A174F1E1 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3417 1096-9896 |
DOI: | 10.1002/path.4411 |