Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion

Zhu, Lingyun; Wang, Xiudong; Wu, Jie; Mao, De-Kui; Xu, Zhishan; He, Zuming; Yu, Aiping

doi:10.3892/or.2012.1851

Cited by 15 publications

(11 citation statements)

References 40 publications

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“…Thrombin also induces release of calcium through RhoA/Rho kinase pathway and activation of myosin light chain (MLC) kinase to inhibit myosin phosphatase, causing a disruption of endothelial barrier function through interactions with actin-myosin [ 16 , 34 ]. Thrombin-induced protein-tyrosine kinase (PTK) affects the phosphorylation of junctional proteins, vascular endothelial-cadherin (VE-cadherin), and catenins and results in migration and proliferation in several tumors such as lung, colon, and gastric cancer [ 35 , 41 – 43 ]. Previous studies have implicated PARs in the development of acute and chronic inflammatory responses as well as thrombin [ 16 , 31 , 35 ].…”

Section: Thrombin-dependent Signaling and Protease-activated Recepmentioning

confidence: 99%

The Characteristics of Thrombin in Osteoarthritic Pathogenesis and Treatment

Chou

Huang

et al. 2014

BioMed Research International

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Osteoarthritis (OA) is a mechanical abnormality associated with degradation of joints. It is characterized by chronic, progressive degeneration of articular cartilage, abnormalities of bone, and synovial change. The most common symptom of OA is local inflammation resulting from exogenous stress or endogenous abnormal cytokines. Additionally, OA is associated with local and/or systemic activation of coagulation and anticoagulation pathways. Thrombin plays an important role in the stimulation of fibrin deposition and the proinflammatory processes in OA. Thrombin mediates hemostatic and inflammatory responses and guides the immune response to tissue damage. Thrombin activates intracellular signaling pathways by interacting with transmembrane domain G protein coupled receptors (GPCRs), known as protease-activated receptors (PARs). In pathogenic mechanisms, PARs have been implicated in the development of acute and chronic inflammatory responses in OA. Therefore, discovery of thrombin signaling pathways would help us to understand the mechanism of OA pathogenesis and lead us to develop therapeutic drugs in the future.

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Section: Thrombin-dependent Signaling and Protease-activated Recepmentioning

confidence: 99%

The Characteristics of Thrombin in Osteoarthritic Pathogenesis and Treatment

Chou

Huang

et al. 2014

BioMed Research International

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“…As implied by its name, PAR1 is activated by proteolytic cleavage of a N-terminal extracellular region by proteases such as thrombin, activated protein C and matrix metalloproteases [ 16 ]. Interestingly, PAR1 expression is increased in breast, lung, ovarian, and prostate cancer [ 17 – 20 ] and PAR1 expression correlates with poor prognosis in breast [ 21 ] and lung cancer [ 22 ]. In line with these clinical data pointing to a tumor-promoting effect of PAR-1, experimental studies underscore the tumor-promoting actions of activated PAR1.…”

Section: Introductionmentioning

confidence: 99%

PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer

et al. 2018

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Protease activated receptor-1 (PAR1) expression is associated with disease progression and overall survival in a variety of cancers. However, the importance of tumor cell PAR1 in pancreatic ductal adenocarcinomas (PDAC) remains unexplored. Utilizing orthotopic models with wild type and PAR1-targeted PDAC cells, we show that tumor cell PAR1 negatively affects PDAC growth, yet promotes metastasis. Mechanistically, we show that tumor cell-specific PAR1 expression correlates with mesenchymal signatures in PDAC and that PAR1 is linked to the maintenance of a partial mesenchymal cell state. Indeed, loss of PAR1 expression results in well-differentiated pancreatic tumors in vivo, with enhanced epithelial characteristics both in vitro and in vivo. Taken together, we have identified a novel growth inhibitory role of PAR1 in PDAC, which is linked to the induction, and maintenance of a mesenchymal-like phenotype. The recognition that PAR1 actively limits pancreatic cancer cell growth suggest that the contributions of PAR1 to tumor growth differ between cancers of epithelial origin and that its targeting should be applied with care.

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“…Moreover, these increased PAR-1 levels are associated with disease progression and reduced overall survival in breast and lung cancer patients (9,10).…”

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confidence: 99%

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

Shi

Damhofer

Daalhuisen

et al. 2017

Mol Med

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Pancreatic cancer is one of the most lethal solid malignancies, with few treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives the progression and induces the chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we address the effects of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth, whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was, however, not as efficient as genetic ablation of PAR-1 in our previous study, suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as monotherapy.

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Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion

Cited by 15 publications

References 40 publications

The Characteristics of Thrombin in Osteoarthritic Pathogenesis and Treatment

The Characteristics of Thrombin in Osteoarthritic Pathogenesis and Treatment

PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

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