Glioma stem cells activate platelets by plasma-independent thrombin production to promote glioblastoma tumorigenesis
Anthony Sloan, Anthony Sloan, Christine Lee, Harry C Hoffman, Peggy L.R. Harris, Theresa E Elder, Brian Richardson, Amber Kerstetter-Fogle, Gino Cioffi, Julia Schroer, Ansh Desai, Mark J. Cameron, Jill S. Barnholtz‐Sloan, Jeremy N. Rich, Eckhard Jankowsky, Anirban Sen Gupta, Andrew E. Sloan, Andrew E. Sloan
Abstract
Abstract Background The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example, glioblastoma (GBM) where metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcomes in many cancers. While platelets are known to promote the progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis. Methods Male and female NSG mice were transplanted with GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines. Results We show that GSCs activate platelets by endogenous production of all the factors of the intrinsic and extrinsic coagulation cascades in a plasma-independent manner. Therefore, GSCs produce thrombin resulting in platelet activation. We further demonstrate that the endogenous coagulation cascades of these cancer stem cells are tumorigenic: they activate platelets to promote stemness and proliferation in vitro and pharmacological inhibition delays tumor growth in vivo. Conclusions Our findings uncover a specific preferential relationship between platelets and GSCs that drive GBM malignancies and identify a therapeutically targetable novel interaction.