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Cancer Discov. 2014 Nov;4(11):1299-309. doi: 10.1158/2159-8290.CD-14-0471. Epub 2014 Aug 19.

Brain tumor cells in circulation are enriched for mesenchymal gene expression.

Author information

1
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
2
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts.
3
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
4
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
5
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Neurology, Harvard Medical School, Boston, Massachusetts.
6
Center for Engineering in Medicine, Harvard Medical School, Boston, Massachusetts.
7
Department of Neurology, Harvard Medical School, Boston, Massachusetts. Department of Radiology, Harvard Medical School, Boston, Massachusetts.
8
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts.
9
Center for Engineering in Medicine, Harvard Medical School, Boston, Massachusetts. Department of Surgery, Harvard Medical School, Boston, Massachusetts.
10
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Surgery, Harvard Medical School, Boston, Massachusetts. maheswaran@helix.mgh.harvard.edu haber@helix.mgh.harvard.edu.
11
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland. maheswaran@helix.mgh.harvard.edu haber@helix.mgh.harvard.edu.

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.

PMID:
25139148
PMCID:
PMC4221467
DOI:
10.1158/2159-8290.CD-14-0471
[Indexed for MEDLINE]
Free PMC Article
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