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• W2091031618 abstract "Platelets have previously been implicated in inflammatory processes, but there is a relatively short literature on their possible role in the progression of cancer. In this issue, Jain, Russell and Ware report that they injected metastatic cell lines into the tail vein of mice, and found that the development of metastases in the lung is impaired in platelet Glycoprotein VI knockout animals. Whilst the observed effect of ablation of the collagen receptor GPVI is partial, resulting in a halving of the number of metastases, this finding offers novel insight into the mechanisms underlying the recruitment of circulating tumor cells to susceptible tissues. How can the platelet exert a pro-metastatic effect? Several possibilities present themselves, for some of which there is experimental evidence. First, the activated platelet may release or generate products that enhance tumor cell survival in the circulation or recruitment to sites of metastasis. One thinks especially of stored platelet alpha granule components that are released upon platelet activation, such as PDGF that might be chemotactic for tumor cells [1] or increase their rate of proliferation. VEGF is similarly released [2] and is a key mediator of tumor angiogenesis. In the present study, however, there was no effect of GPVI knockout on primary tumor mass or its complement of microcapillaries, suggesting that VEGF-mediated enhancement of tumor vascularity should be discounted. The activated platelet is also a rich source of newly-synthesized bioactive materials, including thromboxane A2 and thrombin generated on the activated platelet surface. Some of these products could activate the vessel wall leading to endothelial retraction and increased opportunity for invasion, or may cause vasoconstriction that contributes to the entrapment of circulating tumor cells. Thrombin and other coagulation pathway components have been suggested as mediators of metastasis [3]. Such an indirect, soluble mediator, model would require circulating platelets to become activated, for example by cytokines released by primary tumors, but such mechanisms need not require any direct interaction of tumor cells with the platelet. This is not the first such observation: a greater effect of complete platelet deficiency or PAR4 or fibrinogen knockout [3], or platelet GPIbα deletion [4], has been reported. Both GPIb and GPVI are adhesion receptors that support platelet interaction with collagen, indirectly in the former case via VWF, and directly in the latter. GPVI is a rapid and effective signaling receptor, whilst the VWF/GPIb axis is considered unable to elicit full activation of platelets under most conditions. The greater effect of ablation of GPIb, a weak binder of immobilized VWF at low shear but essential for platelet adhesion at high shear, raises the question of whether the shear rate at the site of platelet activation may be an important determinant of the mediation of metastasis, and suggests that in this system, the capture of platelets rather than their activation is the dominant process. The possibility that platelets or platelet-derived microparticles may adhere to tumor cells and hitch a ride around the circulation until a suitably exposed subendothelial collagen is encountered, in the lung, supports the idea that platelet adhesion receptors play a role in targeting tumor cells to their metastatic niche [3]. Binding to tumor cells might result in platelet activation through GPVI, with consequent enhancement of metastasis through any or all of the mechanisms outlined here. Several direct and indirect ligand–receptor systems might mediate platelet–tumor cell interactions, utilizing, for example, GPIb or GPVI, the two platelet adhesion receptors studied by Jain in this and their previous study. GPIb-bound VWF can interact with RGD-binding integrins, for example αVβ3 that might be expressed on the tumor cell surface, whilst GPVI may bind laminin [5] and thence interact with apposed β1 integrins. Other direct interactions could occur, including that of the epithelial tumor-expressed podoplanin with platelet CLEC-2 [6], or tumor PSGL with P-selectin. The interaction of platelets with tumor cells has been found to perturb the ability of NK cells to target tumor cells [7], possibly by minimizing the scope for intercellular contact. The therapeutic potential of GPVI in metastasis is of obvious interest. Because the bleeding defect in mouse associated with GPVI knockout is minor, and that of GPVI-deficient humans is believed to be modest, it seems quite plausible that the side effects of targeting GPVI would be more acceptable than the serious bleeding that would ensue from targeting either GPIb or fibrinogen. The balance between reduced metastasis and bleeding would need to be considered carefully, but it may be that antagonism of GPVI offers a novel, practical and specific means of minimizing the spread of metastatic tumors. This report [8] of Jain and colleagues needs careful extension if the underlying mechanism is to be identified, and then a balanced judgment on the potential of platelet GPVI as a metastatic target may be possible. The author states that he has no conflict of interest." @default.
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• W2091031618 date "2009-10-01" @default.
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• W2091031618 title "Platelet glycoprotein VI as a mediator of metastasis" @default.
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• W2091031618 doi "https://doi.org/10.1111/j.1538-7836.2009.03566.x" @default.
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