| Abstract: | The tumor architecture of high-grade gliomas is shaped by tumor cell
necrosis, invasive growth, and the leakage of a fibrin-rich edema from
poorly organized tumor blood vessels. In this study, we demonstrate a
marked upregulation of clot formation in the interstitial spaces of tumor
tissues from patients with glioblastoma (GBM) whereas a tumor-free brain
is essentially devoid of fibrin. The accumulation of fibrin in tumor interstitial spaces is functionally relevant as we demonstrate increased infiltration and growth of primary GBM cells after embedding in a 3-dimensional
matrix made of fibrin ex vivo. Additionally, we detected accelerated tumor
growth after implanting GBM cells together with clotted plasma in brains
of immunodeficient mice whereas GBM development in clotting-deficient
hemophilia mice was delayed. GBM growth correlated with the outgrowth
of invadopodia and their adhesive interactions with the 3-dimensional clot
matrix, which was mediated by integrins β1 and β3 and their common
downstream target focal adhesion kinase (FAK). Knocking down FAK with
CRISPR Cas9 caused an upregulation of p21/p27 cell-cycle inhibitors,
strong growth inhibition in cultured GBM cells, and sustained antitumorigenic effects in orthotopic GBM xenografts in vivo. These results go
hand in hand with genomic data from The Cancer Genome Atlas that
indicate increased clotting activity and reduced patient survival in glioma
subgroups with high integrin β1 and β3 expression. We therefore conclude
that clotting in glioma interstitial spaces provides tumor cells with a potent
proliferative stimulus that can be reversed by targeting the adhesive machinery of GBM cells via inhibition of FAK.
Significance: High-grade gliomas are associated with intratumoral
thrombosis, tumor cell necrosis, and hemorrhage. The resulting blood
clot serves as an adhesive matrix for glioma cell integrins that activate
FAK. Knocking down FAK with CRISPR cas9, on the other hand, is
highly effective at halting GBM growth in mice. |
