Abstract Number: PB0732
Meeting: ISTH 2022 Congress
Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by invasive growth and the leakage of a fibrin-rich edema into tumor interstitial spaces from poorly organized tumor blood vessels.
Aims: To test if clotted plasma supports GBM progression.
Methods: We assessed fibrin formation in astrocytoma samples from patients using immunohistochemistry and examined the effect of plasma clot on glioblastoma growth in mice in vivo. Glioblastoma cells embedded in 3-D fibrin were analyzed for invasion and growth using live cell imaging and deconvolution microscopy. In order to assess clinical relevance, we analyzed primary cells and tissue arrays.
Results: We demonstrate a marked upregulation of clot formation in the interstitial spaces of astrocytoma patients while tumor-free brain is essentially devoid of fibrin. This is relevant as we detected a delay of glioblastoma development in clotting-deficient hemophilia mice and accelerated tumor growth in nude mice after implanting glioblastoma cells in conjunction with clotted plasma. This growth promoting effect was reproducible when we cultured GBM cells in a 3-dimensional matrix of clotted plasma in vitro. The pro-growth effect of the clotted plasma resulted from adhesive interactions with integrins on GBM cells, which in turn promoted the activation of focal adhesion kinase and p42/Erk. In addition, engagement of integrins promoted the formation of actin-rich invadopodia and subsequent locomotion of GBM cells. Invadopodia formation in clotted plasma was also evident in primary tumor cells from patients with astrocytoma 2 and 3 but only primary GBM cells were able to grow sufficiently in 3D clot. Finally, overexpression of focal adhesion kinase-activating integrins in glioma tissues from patients was associated with a significantly decreased overall survival.
Conclusion(s): The deposition of clotted plasma in tumor interstitial spaces promotes infiltration and proliferation of glioblastoma cells and, therefore, may provide a therapeutic target to combat primary brain tumors.
To cite this abstract in AMA style:Knowles L, Wolter C, Ketter R, Urbschat S, Linsler S, Müller S, Müller A, Zhou X, Qu B, Hermann E, Pilch J. Fibrin Promotes Glioblastoma Progression via Focal Adhesion Kinase [abstract]. https://abstracts.isth.org/abstract/fibrin-promotes-glioblastoma-progression-via-focal-adhesion-kinase/. Accessed September 26, 2022.
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