Protease-activated receptors in cancer: A systematic review

Han, Na; Jin, Ketao; He, Kuifeng; Cao, Jiashu; Teng, Lisong

doi:10.3892/ol.2011.291

Cited by 44 publications

(34 citation statements)

References 152 publications

(158 reference statements)

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“…Studies using synthetic PAR-selective peptide agonists and PAR knockout mice models have been valuable in elucidating the importance of PAR subtype activity in particular disease processes. Well established roles for PARs include platelet activation that precedes thrombosis [18], cancer invasion and metastasis [19] and activation of pivotal pathways that promote acute and chronic inflammation (e.g. arthritis) [20].…”

Section: Mechanisms Of Par Cleavage and Activationmentioning

confidence: 99%

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Cunningham

McIntosh

Bushell

et al. 2016

Biochemical Society Transactions

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Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date.

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Section: Mechanisms Of Par Cleavage and Activationmentioning

confidence: 99%

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Cunningham

McIntosh

Bushell

et al. 2016

Biochemical Society Transactions

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“…Surprisingly, although thrombin is the most potent physiological agonist known and is highly elevated in several pathological conditions where angiogenesis occurs (e.g. cancer and inflammation) (Martorell et al ., ; Han et al ., ), its action on the release of angiogenesis‐modulating factors from platelet granules is still a matter of controversy.…”

Section: Introductionmentioning

confidence: 99%

Platelet‐mediated angiogenesis is independent of VEGF and fully inhibited by aspirin

Etulain

Fondevila

Negrotto

et al. 2013

British J Pharmacology

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Background and Purpose Platelets are major players in every step of vessel development through the local delivery of angiogenesis‐modulating factors, including the pro‐angiogenic protein VEGF and the anti‐angiogenic endostatin. Although thrombin is a potent agonist and is highly elevated in angiogenesis‐related diseases, studies regarding its action on the release of platelet angiogenic factors are scarce and controversial. Herein, we have investigated the role of thrombin not only in VEGF and endostatin release but also in net platelet angiogenic activity. Experimental Approach Human platelets were stimulated with thrombin in the presence of the various inhibitors of the signalling pathways involved in platelet activation. Supernatants/releasates were used to determine the levels of angiogenic molecules and to induce angiogenic responses. Key Results We found that thrombin induced the secretion of both VEGF and endostatin; however, the overall effect of the releasates was pro‐angiogenic as they promoted tubule‐like formation and increased the proliferation of endothelial cells. Both responses were only slightly suppressed in the presence of a VEGF receptor‐neutralizing antibody. Pharmacological studies revealed that while inhibitors of PKC, p38, ERK1/2, Src kinases or PI3K/Akt exerted only partial inhibitory effects, aspirin fully blocked the pro‐angiogenic activity of the releasate. Conclusions and Implications In contrast to current belief, platelet pro‐angiogenic responses are independent of VEGF and appear to be the result of the combined action of several molecules. Moreover, our data reinforce the notion that aspirin is a good candidate for a therapeutic agent to treat angiogenesis‐related diseases.

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“…Disseminated tumor cells use different extravasation mechanisms. ( A ) Tumor cells can activate the coagulation system and generate thrombin from its precursor, prothrombin, at sites of metastasis 23 . Activation of the thrombin receptor PAR-1 on endothelial cells leads to G protein-mediated activation of RhoA and RhoA downstream signaling components that converge on the increase of actomyosin contractility and cell-cell junction remodeling.…”

mentioning

confidence: 99%

CCL2 at the crossroad of cancer metastasis

Eferl

2013

JAK-STAT

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Primary tumors can affect organ functions, either mechanically when they grow to a considerable size or via production of hormones. However, mortality of cancer patients is in most cases due to formation of secondary growths.1,2 Consequently, various drugs are currently employed in clinical trials to impair specific steps of cancer metastasis such as mesenchymal or amoeboid cell migration, intravasation and/or colonization.2 From the clinical point of view, targeting late metastatic processes such as extravasation or colonization might be required for cancer patients that bear already dormant micrometastases in their capillaries which have left behind earlier metastatic steps. Development of such drugs needs characterization of molecular targets implicated in distinct steps of cancer metastasis.

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Protease-activated receptors in cancer: A systematic review

Cited by 44 publications

References 152 publications

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Platelet‐mediated angiogenesis is independent of VEGF and fully inhibited by aspirin

CCL2 at the crossroad of cancer metastasis

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