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Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall

Shengwen Calvin Li145*, Long T Vu15, Hector W Ho23, Hong Zhen Yin4, Vic Keschrumrus1, Qiang Lu7, Jun Wang7, Heying Zhang7, Zhiwei Ma6, Alexander Stover8, John H Weiss4, Philip H Schwartz89 and William G Loudon123

Author Affiliations

1 Neuro-Oncology Research Laboratory, Center for Neuroscience and Stem Cell Research, Children's Hospital of Orange County (CHOC) Research Institute, 455 South Main Street, Orange, CA 92868, USA

2 Department of Neurological Surgery, Saint Joseph Hospital, Orange, CA, 92868, USA

3 Department of Neurological Surgery, University of California Irvine, Orange, CA, 92862, USA

4 Department of Neurology, University of California Irvine, Orange, CA 92862, USA

5 Department of Biological Science, California State University, Fullerton, CA, 92834, USA

6 Department of Pathology and Laboratory Medicine, Good Samaritan Hospital Medical Center, 1000 Montauk Highway, West Islip, NY, 11795, USA

7 Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

8 National Human Neural Stem Cell Resource, Center for Neuroscience and Stem Cell Research, CHOC Children's Hospital Research Institute, 455 South Main Street, Orange, CA, 92868, USA

9 Developmental Biology Center, University of California Irvine, Irvine, CA, 92612, USA

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Cancer Cell International 2012, 12:41  doi:10.1186/1475-2867-12-41

Published: 20 September 2012

Abstract

Background

The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall.

Methods

We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques.

Results

The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice.

Conclusions

This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely the driving force for the rapid recurrence of the tumor in the patient.

Keywords:
Glioblastoma multiforme; Primary tumors; Brain tumor stem cells; Cancer stem cells; Organotypic brain slice culture