Protease-activated receptor 2 suppresses lymphangiogenesis and subsequent lymph node metastasis in a murine pancreatic cancer model

Abstract

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.

Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer‐associated fibroblasts by paracrine activation of protease‐activated receptor 2

“…When injected intravenously, F2rl1 +/+ B16 melanoma cells formed lung metastases with no difference in frequency or size between F2rl1 −/− and F2rl1 +/+ hosts . In a murine pancreatic cancer model, ablation of PAR‐2 from the stromal compartment inhibited primary tumor growth but enhanced lymphangiogenesis and lymph node metastasis . Therefore, the role of stromal PAR‐2 in cancer progression may depend on the primary tumor type, the model of metastatic induction and the pericellular microenvironment.…”

Proteinase-activated receptor 2 promotes TGF-β-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-β type I receptor ALK5

“…However, PAR2 has also been shown to drive tumour growth in murine models of mammary adenocarcinoma [14] and pancreatic cancer. Silencing F2RL1 in a PDAC cell line by RNA interference or genetically ablating it from the stromal compartment dramatically suppressed the growth of subcutaneous tumour xenografts and of orthotopically growing primary tumours, respectively [15, 16]. …”

The lymphatic system and pancreatic cancer

“…A recent study by Shi, et al highlights an additional protease-related mechanism by which CAFs may influence pancreatic cancer progression and lymphatic metastasis. Specific pancreatic stromal compartment deletion of protease-activated receptor-2 (PAR-2), a GPCR highly expressed in PDAC, resulted in decreased primary tumor size (due to anti-angiogenesis effects) but increased LVD and lymph node metastases [238]. …”