Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology

Abstract

Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors.Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of "tumor education", characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, Cells 2020, 9, 294 2 of 15 S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network's complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.

Trauma Coagulopathy and Its Outcomes

“…Unlike other pathologies [24,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], the molecular mechanism underlying the pathophysiology of acquired coagulopathy is still not well known, although studies have reported that a few bioumoral parameters (pH, lactates, and BE) are significantly more compromised in trauma coagulopathy patients [24,32,48]. Because ours was not a pathophysiological study, we do not know whether this correlation stems from the fact that MT results more easily in coagulopathy or whether trauma coagulopathy increases the severity of the trauma itself or whether there is a mutual influence.…”

Trauma-Induced Coagulopathy: Overview of an Emerging Medical Problem from Pathophysiology to Outcomes

“…The identification and management of patients pre-treated with anticoagulant agents, especially direct anticoagulant, continues to pose a major challenge despite accumulating experience and awareness [ 12 , 14 , 15 , 16 , 17 , 44 , 59 , 74 , 101 , 102 , 103 , 122 , 154 , 155 , 156 , 157 , 158 , 159 ]. Idarucizumab is indicated as an antidote for the thrombin inhibitor dabigatran (5 g intravenously (R35/1B).…”

“…Blood product optimal use procedures continue to evolve, and their development should be goal directed. Despite greater awareness and experience, the identification and management of patients under the effects of anti-coagulant agents remains a major challenge [12,[14][15][16][17]59,74,[101][102][103]122,[154][155][156][157][158][159]162].…”

Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I)

“…Intrinsic glioma cell heterogenicity, high mitotic activity, abnormal angiogenesis, and early local recurrence are responsible for the resilience of these tumors toward standard treatments [ 9 , 10 , 11 ]. Despite the biological complexity and adaptive nature of these lethal neoplasms, recent studies have identified some molecular and epigenetic markers, such as isocitrate dehydrogenase and O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter, which are useful for predicting the prognosis and planning new targeted therapeutic options [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Moreover, the detection of glioma immunogenomics, alongside immunosuppressive mechanisms within the tumor microenvironment, has prompted the development of new immunotherapies [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”