ABSTRACT
Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches. GSC interactions with their niche influence self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the integrin αvß8 and its latent transforming growth factor ß1 (TGFß1) protein ligand have central roles in promoting niche co-option and GBM initiation. αvß8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Fractionation of ß8high cells from freshly resected human GBM samples also reveals a requirement for this integrin in tumorigenesis in vivo. Whole-transcriptome sequencing reveals that αvß8 integrin regulates tumor development, in part, by driving TGFß1-induced DNA replication and mitotic checkpoint progression. Collectively, these data identify the αvß8 integrin-TGFß1 signaling axis as crucial for exploitation of the perivascular niche and identify potential therapeutic targets for inhibiting tumor growth and progression in patients with GBM.
Subject(s)
Brain Neoplasms/pathology , Carcinogenesis/metabolism , Glioblastoma/pathology , Integrins/metabolism , Neoplastic Stem Cells/metabolism , Transforming Growth Factor beta1/metabolism , AC133 Antigen/metabolism , Animals , Biomarkers, Tumor/metabolism , Cell Differentiation , Cell Line, Tumor , Cell Self Renewal , Disease Progression , Humans , Integrin beta Chains/metabolism , M Phase Cell Cycle Checkpoints , Mice , Mice, SCID , Primary Cell Culture , SOXB1 Transcription Factors/metabolism , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
Angiogenesis involves a complex set of cell-cell and cell-extracellular matrix (ECM) interactions that coordinately promote and inhibit blood vessel growth and sprouting. Although many factors that promote angiogenesis have been characterized, the identities and mechanisms of action of endogenous inhibitors of angiogenesis remain unclear. Furthermore, little is known about how cancer cells selectively circumvent the actions of these inhibitors to promote pathological angiogenesis, a requisite event for tumor progression. Using mosaic mouse models of the malignant brain cancer, astrocytoma, we report that tumor cells induce pathological angiogenesis by suppressing expression of the ECM protein receptor alphavbeta8 integrin. Diminished integrin expression in astrocytoma cells leads to reduced activation of latent TGFbetas, resulting in impaired TGFbeta receptor signaling in tumor-associated endothelial cells. These data reveal that astrocytoma cells manipulate their angiogenic balance by selectively suppressing alphavbeta8 integrin expression and function. Finally, these results show that an adhesion and signaling axis normally involved in developmental brain angiogenesis is pathologically exploited in adult brain tumors.
