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J. Biol. Chem., Vol. 278, Issue 18, 15951-15957, May 2, 2003
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From the Departments of We employed a genetically defined
human cancer model to investigate the contributions of two genes
up-regulated in several cancers to phenotypic changes associated with
late stages of tumorigenesis. Specifically, tumor cells expressing two
structurally unrelated bone-related genes, osteonectin and
osteoactivin, acquired a highly invasive phenotype when implanted
intracranially in immunocompromised mice. Mimicking a subset of
gliomas, tumor cells invaded brain along blood vessels and developed
altered vasculature at the brain-tumor interface, suggesting that
production of those two proteins by tumor cells may create a complex
relationship between invading tumor and vasculature co-opted during
tumor invasion. Interestingly, the same tumor cells formed massive
spontaneous metastases when implanted subcutaneously. This dramatic
alteration in tumor phenotype indicates that cellular microenvironment
plays an important role in defining the specific effects of those gene
products in tumor behavior. In vitro examination of tumor
cells expressing either osteonectin or osteoactivin revealed that there
was no impact on cellular growth or death but increased
invasiveness and expression of MMP-9 and MMP-3. Specific pharmacologic
inhibitors of MMP-2/9 and MMP-3 blocked the increased in
vitro invasion associated with osteoactivin expression, but only
MMP-3 inhibition altered the invasive in vitro
phenotype mediated by osteonectin. Results from this genetically
defined model system are supported by similar findings obtained from
several established tumor cell lines derived originally from human
patients. In sum, these results reveal that the expression of a single
bone-related gene can dramatically alter or modify tumor cell behavior
and may confer differential growth characteristics in different
microenvironments. Genetically defined human cancer models offer useful
tools in functional genomics to define the roles of specific
genes in late stages of carcinogenesis.
Bone-related Genes Expressed in Advanced Malignancies Induce
Invasion and Metastasis in a Genetically Defined Human Cancer
Model*
§,
,,,§§, and Medicine, ¶ Surgery,
Pathology, ** Pharmacology and Cancer Biology, and
Radiation Oncology, Duke University Medical Center,
Durham, North Carolina 27710
*
This work was supported by National Institutes of Health
Grants K08 NS02055 (to J. N. R.), R01 CA83770 (to X.-F. W.), R01 CA94184 and CA82481 (to C. M. C.), and NS20023 (to D. D. B.); a
grant from the Pediatric Brain Tumor Foundation (to J. N. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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