Novel antiplatelet strategies targeting GPVI, CLEC-2 and tyrosine kinases

Harbi, Maan H.; Smith, Christopher W.; Nicolson, Phillip L.R.; Watson, Steve P.; Thomas, Mark R.

doi:10.1080/09537104.2020.1849600

Cited by 35 publications

(37 citation statements)

References 149 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the primary contact between tumor cells and platelets likely is mediated by the Clec-2-podoplanin interaction, targeting this early step should substantially impede the entire TCPA formation cascade. Accordingly, several approaches are being followed to identify inhibitors of Clec-2 and podoplanin (Harbi et al, 2021). Among the Clec-2 targeting toxins, the snake venom rhodocytin, also named aggretin, was the first to be discovered (Suzuki- Inoue et al, 2006).…”

Section: Perspectives For Translation Into Clinical Treatment Strategiesmentioning

confidence: 99%

“…Cobalt hematoporphyrin was identified by screening a chemical compound library for inhibitors of the interaction between recombinant expressed Clec-2 and podoplanin (Tsukiji et al, 2018). When cobalt hematoporphyrin was used in a mouse model, podoplanin-induced pulmonary metastasis was blocked efficiently (Tsukiji et al, 2018), however, at a potency yet too low for clinical application (Harbi et al, 2021). In a similar approach the 5-nitrobenzoate compound 2CP was discovered as another inhibitor of the Clec-2-podoplanin interaction (Chang et al, 2015).…”

Section: Perspectives For Translation Into Clinical Treatment Strategiesmentioning

confidence: 99%

See 1 more Smart Citation

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Obermann

Brockhaus

Eble

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Although platelets and the coagulation factors are components of the blood system, they become part of and contribute to the tumor microenvironment (TME) not only within a solid tumor mass, but also within a hematogenous micrometastasis on its way through the blood stream to the metastatic niche. The latter basically consists of blood-borne cancer cells which are in close association with platelets. At the site of the primary tumor, the blood components reach the TME via leaky blood vessels, whose permeability is increased by tumor-secreted growth factors, by incomplete angiogenic sprouts or by vasculogenic mimicry (VM) vessels. As a consequence, platelets reach the primary tumor via several cell adhesion molecules (CAMs). Moreover, clotting factor VII from the blood associates with tissue factor (TF) that is abundantly expressed on cancer cells. This extrinsic tenase complex turns on the coagulation cascade, which encompasses the activation of thrombin and conversion of soluble fibrinogen into insoluble fibrin. The presence of platelets and their release of growth factors, as well as fibrin deposition changes the TME of a solid tumor mass substantially, thereby promoting tumor progression. Disseminating cancer cells that circulate in the blood stream also recruit platelets, primarily by direct cell-cell interactions via different receptor-counterreceptor pairs and indirectly by fibrin, which bridges the two cell types via different integrin receptors. These tumor cell-platelet aggregates are hematogenous micrometastases, in which platelets and fibrin constitute a particular TME in favor of the cancer cells. Even at the distant site of settlement, the accompanying platelets help the tumor cell to attach and to grow into metastases. Understanding the close liaison of cancer cells with platelets and coagulation factors that change the TME during tumor progression and spreading will help to curb different steps of the metastatic cascade and may help to reduce tumor-induced thrombosis.

show abstract

Section: Perspectives For Translation Into Clinical Treatment Strategiesmentioning

confidence: 99%

Section: Perspectives For Translation Into Clinical Treatment Strategiesmentioning

confidence: 99%

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Obermann

Brockhaus

Eble

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Furthermore, acquired and inherited loss of GPVI, though the latter being rare, resulted in a mild bleeding disorder 14 and left adhesion to collagen intact 15 . Due to this differential role of GPVI in thrombosis and hemostasis, GPVI has been proposed as a promising anti‐thrombotic target 16,17 . However, the lack of a severe bleeding phenotype has puzzled platelet scientists.…”

Section: Introductionmentioning

confidence: 99%

“…15 Due to this differential role of GPVI in thrombosis and hemostasis, GPVI has been proposed as a promising anti-thrombotic target. 16,17 However, the lack of a severe bleeding phenotype has puzzled platelet scientists. Proposed explanations include redundancy with alternative collagen receptors (integrin α 2 β 1 ), other platelet receptors (CLEC2), and different subendothelial ligands for platelets (laminin, fibronectin, podoplanin).…”

mentioning

confidence: 99%

GPR56, a novel platelet collagen receptor that loves stress

Hers

Mundell

2021

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Platelets interact with the injured vasculature and/or ruptured atherosclerotic plaque through adhesion receptors. Upon vascular injury, the underlying extracellular matrix, of which collagen type III is a major component, becomes exposed to the blood circulation and allows platelets to adhere and become activated. At arterial shear rate, this process is mediated through the interaction of platelet GPIb with collagen-bound von Willebrand factor (VWF), allowing platelets to be recruited from the blood stream. Subsequent activation by collagen results in shape change, cell spreading, release of secondary mediators such as adenosine diphosphate (ADP) and thromboxane A 2 (TxA 2 ), and integrin α IIb β 3 activation. The latter allows fibrinogen binding and bridging of platelets together to form a thrombus.The first positive identification of a platelet collagen receptor came from a patient deficient in glycoprotein (GP)Ia, whose platelets failed to respond to collagen. 1 GPIa, as part of the GPIa/IIa complex (integrin α 2 β 1 ), was subsequently confirmed to be a collagen receptor 2 , and deficiency resulted in a complete loss of collagen-induced aggregation. GPIa deficiency, however, only delayed in vivo thrombus formation and had no effect on bleeding time. 3 Integrin α 2 β 1 was shown to support firm adhesion to collagen under flow. 4 Multiple groups suggested the existence of an additional GP collagen receptor with a molecular weight of around 60-65 kDa, 5-7 which was later identified as GPVI. 8 Subsequent cloning of the GP6 gene for GPVI

show abstract

“…thrombosis, would also be fascinating to study. TKIs already have inhibiting effects on platelets mainly via the GPVI pathway, therefore, these drugs might be possible to use as anti-platelet drugs in (deep vein) thrombosis, which is also suggested recently by other studies 96,97 . These TKIs are already approved in the clinic, ergo easier to test in other diseases involving thrombosis or thrombo-inflammation, in a short period of time as side effects are already reported.…”

Section: Future Perspectivesmentioning

confidence: 66%

Tyrosine kinase inhibitors for cancer treatment

Tullemans

View full text Add to dashboard Cite

Platelets can contribute to tumour progression and metastasis. Cancer patients are at increased risk of thrombosis, while advanced stages of cancer associate with thrombocytosis or increased platelet reactivity. Tyrosine kinase inhibitors (TKIs) are widely used as a targeted strategy for cancer treatment, aiming to prolong progression-free survival of the patients. Because of their broad kinase target spectrum, most TKIs inevitably have off-target effects. Platelets rely on on tyrosine kinase activity for their activation. Frequently observed side effects are lowering of platelet count and inhibition of platelet functions, whether or not accompanied by an increased bleeding risk. In this review we aim to give insight into: (i) 38 TKIs that are currently used for treatment of different types of cancer, either on the market or in clinical trials, (ii) how distinct TKIs can inhibit activation mechanisms in platelets, and (iii) the clinical consequences of the antiplatelet effects due to TKI treatment. For several TKIs, the knowledge on affinity for their targets does not align with published effects on platelets and reported bleeding events. Together, this review should raise awareness of the potential antiplatelet effects of several TKIs, which will be enhanced in the presence of antithrombotic drugs.Integrin-dependent signalling. Platelet integrins, in particular α IIb β 3 , α 2 β 1 and αƲβ 3 , regulate adhesion, aggregation and thrombus formation 28 . Especially regarding integrin α IIb β 3 (ligands: fibrinogen, vWF and other matrix proteins) much research has been performed to the outside-in signalling events triggered by the occupied, activated conformation. Several tyrosine kinases are implicated in this signalling pathway, including FAK, Pyk2, Src, SLP76 and Syk 29, 31 .

show abstract

Novel antiplatelet strategies targeting GPVI, CLEC-2 and tyrosine kinases

Cited by 35 publications

References 149 publications

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

GPR56, a novel platelet collagen receptor that loves stress

Tyrosine kinase inhibitors for cancer treatment

Contact Info

Product

Resources

About