Brain Tumor Cells in Circulation Are Enriched for Mesenchymal Gene Expression
- 1 November 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 4 (11), 1299-1309
- https://doi.org/10.1158/2159-8290.cd-14-0471
Abstract
Glioblastoma (GBM) is a highly aggressive brain cancer characterized by local invasion and angiogenic recruitment, yet metastatic dissemination is extremely rare. Here, we adapted a microfluidic device to deplete hematopoietic cells from blood specimens of patients with GBM, uncovering evidence of circulating brain tumor cells (CTC). Staining and scoring criteria for GBM CTCs were first established using orthotopic patient-derived xenografts (PDX), and then applied clinically: CTCs were identified in at least one blood specimen from 13 of 33 patients (39%; 26 of 87 samples). Single GBM CTCs isolated from both patients and mouse PDX models demonstrated enrichment for mesenchymal over neural differentiation markers compared with primary GBMs. Within primary GBMs, RNA in situ hybridization identified a subpopulation of highly migratory mesenchymal tumor cells, and in a rare patient with disseminated GBM, systemic lesions were exclusively mesenchymal. Thus, a mesenchymal subset of GBM cells invades the vasculature and may proliferate outside the brain. Significance: GBMs are locally invasive within the brain but rarely metastasize to distant organs, exemplifying the debate over “seed” versus “soil.” We demonstrate that GBMs shed CTCs with invasive mesenchymal characteristics into the circulation. Rare metastatic GBM lesions are primarily mesenchymal and show additional mutations absent in the primary tumor. Cancer Discov; 4(11); 1299–1309. ©2014 AACR. See related commentary by Seoane and De Mattos-Arruda, p. 1259 This article is highlighted in the In This Issue feature, p. 1243Other Versions
This publication has 31 references indexed in Scilit:
- A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2αBrain, 2010
- Isolation and Characterization of Circulating Tumor Cells from Patients with Localized and Metastatic Prostate CancerScience Translational Medicine, 2010
- Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1Cancer Cell, 2010
- A multigene predictor of outcome in glioblastomaNeuro-Oncology, 2009
- Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus VectorsCancer Research, 2009
- A gene regulatory network orchestrates neural crest formationNature Reviews Molecular Cell Biology, 2008
- The 2007 WHO Classification of Tumours of the Central Nervous SystemActa Neuropathologica, 2007
- Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesisCancer Cell, 2006
- Histology-Based Expression Profiling Yields Novel Prognostic Markers in Human GlioblastomaJournal of Neuropathology and Experimental Neurology, 2005
- Contiguous glioblastoma multiforme and fibrosarcoma with extracranial metastasisCancer, 1969