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Etiology and Pathogenesis
> Cancer
Stem Cells
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Cancer Research 66, 7843-7848, August 15, 2006
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Abstract |
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Stem Cell僕ike Glioma Cells Promote
Tumor Angiogenesis through Vascular Endothelial Growth Factor
Shideng Bao1,5,
Qiulian Wu1,5, Sith
Sathornsumetee1,5, Yueling
Hao1,5, Zhizhong
Li6, Anita B.
Hjelmeland1,5, Qing
Shi1,5, Roger E.
McLendon2, Darell
D. Bigner1,2,5 and Jeremy
N. Rich1,3,4,5,6
Departments of 1 Surgery,
2 Pathology, 3 Medicine, and 4
Neurobiology; 5 Preston Robert Tisch Brain Tumor Center;
and 6 Molecular Cancer Biology Program, Duke University
Medical Center, Durham, North Carolina -- Requests for reprints:
Jeremy N. Rich, Preston Robert Tisch Brain Tumor Center, Duke
University Medical Center, Box 2900, Durham, NC 27710. Phone:
919-681-1693; Fax: 919-684-6514; E-mail: rich0001@mc.duke.edu.
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Malignant gliomas are highly lethal
cancers dependent on angiogenesis.
Critical tumor subpopulations within gliomas share characteristics
with neural stem cells.
We examined the potential of stem cell僕ike glioma cells
(SCLGC) to support tumor angiogenesis.
SCLGC isolated from human glioblastoma biopsy specimens and
xenografts potently generated tumors when implanted into
the brains of immunocompromised mice, whereas non-SCLGC
tumor cells isolated from only a few tumors formed
secondary tumors when xenotransplanted.
Tumors derived from SCLGC were morphologically
distinguishable from non-SCLGC tumor populations by
widespread tumor angiogenesis, necrosis, and
hemorrhage.
To determine a potential molecular mechanism for SCLGC in
angiogenesis, we measured the expression of a panel of
angiogenic factors secreted by SCLGC.
In comparison with matched non-SCLGC populations, SCLGC
consistently secreted markedly elevated levels of vascular
endothelial growth factor (VEGF), which were further
induced by hypoxia.
In an in vitro model of angiogenesis, SCLGC-conditioned
medium significantly increased endothelial cell migration
and tube formation compared with non-SCLGC tumor
cell膨onditioned medium.
The proangiogenic effects of glioma SCLGC on endothelial
cells were specifically abolished by the anti-VEGF
neutralizing antibody bevacizumab, which is in clinical use
for cancer therapy.
Furthermore, bevacizumab displayed potent antiangiogenic
efficacy in vivo and suppressed growth of xenografts
derived from SCLGC but limited efficacy against xenografts
derived from a matched non-SCLGC population.
Together these data indicate that stem cell僕ike tumor cells
can be a crucial source of key angiogenic factors in cancers and
that targeting proangiogenic factors from stem cell僕ike tumor
populations may be critical for patient therapy.
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ｩ 2006 American Association for Cancer
Research
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Abstract
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