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Etiology and Pathogenesis
> Invasion
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Cancer Research 66, 11771-11780, December 15, 2006. doi:
10.1158/0008-5472.CAN-05-0470
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Abstract |
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Tenascin-C Stimulates Glioma Cell
Invasion through Matrix Metalloproteinase-12
Susobhan Sarkar1,
Robert K. Nuttall3,
Shuhong Liu1, Dylan
R. Edwards3 and V.
Wee Yong1,2
Departments of 1Oncology
and 2Clinical Neurosciences, University of Calgary,
Calgary, Alberta, Canada and 3 School of Biological
Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom
-- Requests for reprints: V. Wee Yong, Departments of Oncology and
Clinical Neurosciences, University of Calgary, 3330 Hospital Drive,
Calgary, Alberta, Canada T2N 4N1. Phone: 403-220-3544; Fax:
403-283-8731; E-mail: vyong@ucalgary.ca .
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The capacity of glioma cells to invade
extensively within the central nervous system is a major
cause of the high morbidity rate of primary malignant brain
tumors.
Glioma cell invasion involves the attachment of tumor cells
to extracellular matrix (ECM), degradation of ECM
components, and subsequent penetration into adjacent brain
structures.
These processes are accomplished in part by matrix
metalloproteinases (MMP) within a three-dimensional milieu
of the brain parenchyma.
As the majority of studies have used a two-dimensional
monolayer culture system, we have used a three-dimensional
matrix of collagen type I gel to address glioma-secreted
proteases, ECM, and invasiveness of glioma cells.
We show that in a three-dimensional collagen type I matrix, the
presence of tenascin-C, commonly elevated in high-grade gliomas,
increased the invasiveness of glioma cells.
The tenascin-C–mediated invasiveness was blocked by
metalloproteinase inhibitors, but this did not involve the
gelatinases (MMP-2 and MMP-9) commonly implicated in
two-dimensional glioma growth.
A thorough analysis of 21 MMPs and six members of a
disintegrin and metalloproteinase domain showed that MMP-12
was increased in gliomas by tenascin-C in three-dimensional
matrix.
Furthermore, examinations of resected specimens revealed
high MMP-12 levels in the high-grade glioblastoma multiforme
tumors.
Finally, a function-blocking antibody as well as small
interfering RNA to MMP-12 attenuated the tenascin-C–stimulated glioma
invasion.
These results identify a new factor, MMP-12, in regulating
glioma invasiveness through interaction with tenascin-C.
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© 2006 American Association for Cancer
Research
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Abstract |
Reprint
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