Abstract
Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs) and spheroid cultures of GSCs (Sp-GSCs) had high expression of stem cell markers (CD133, Sox2 and Nestin), but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein). In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention.
Highlights
Brain tumors represent an important cause of cancer-related morbidity and mortality in the United States, with malignant gliomas being among the most aggressive and difficult to treat [1]
To more fully characterize the molecular signatures of these glioblastoma stem-like cell (GSC) populations, RNA was prepared from biological replicates of GBM6 cells grown as either short term cultures of differentiated bulk tumor cells, Ad-GSCs, or spheroid cultures of GSCs (Sp-GSCs), and whole genome expression profiling was performed on HT-12 expression Bead-Chips by the UTHSC Center of Genomics and Bioinformatics
Consistent with our previous findings [25], high Nestin, Sox2 and CD133 expression was found in both GSC populations, while βIII-tubulin and glial fibrillary acid protein was expressed at relatively low levels
Summary
Brain tumors represent an important cause of cancer-related morbidity and mortality in the United States, with malignant gliomas being among the most aggressive and difficult to treat [1]. They rarely metastasize, malignant gliomas are locally invasive, highly vascular tumors with extensive areas of necrosis and hypoxia. The prognosis for patients with glioma is poor. Most patients with glioblastoma multiforme (GBM), the most severe grade of glioma (WHO grade IV) and the most common glioma subtype in adults, die within 2 years of diagnosis, and patient survival has remained dismally low for decades [1]. Patients with recurrent GBM have an even bleaker prognosis [3]
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