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Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model.

Publication ,  Journal Article
Rich, JN; Shi, Q; Hjelmeland, M; Cummings, TJ; Kuan, C-T; Bigner, DD; Counter, CM; Wang, X-F
Published in: J Biol Chem
May 2, 2003

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.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 2, 2003

Volume

278

Issue

18

Start / End Page

15951 / 15957

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Proteins
  • Osteonectin
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Mice, SCID
  • Mice
  • Membrane Glycoproteins
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 3
 

Citation

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Rich, J. N., Shi, Q., Hjelmeland, M., Cummings, T. J., Kuan, C.-T., Bigner, D. D., … Wang, X.-F. (2003). Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem, 278(18), 15951–15957. https://doi.org/10.1074/jbc.M211498200
Rich, Jeremy N., Qing Shi, Mark Hjelmeland, Thomas J. Cummings, Chien-Tsun Kuan, Darell D. Bigner, Christopher M. Counter, and Xiao-Fan Wang. “Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model.J Biol Chem 278, no. 18 (May 2, 2003): 15951–57. https://doi.org/10.1074/jbc.M211498200.
Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan C-T, Bigner DD, et al. Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem. 2003 May 2;278(18):15951–7.
Rich, Jeremy N., et al. “Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model.J Biol Chem, vol. 278, no. 18, May 2003, pp. 15951–57. Pubmed, doi:10.1074/jbc.M211498200.
Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan C-T, Bigner DD, Counter CM, Wang X-F. Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem. 2003 May 2;278(18):15951–15957.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 2, 2003

Volume

278

Issue

18

Start / End Page

15951 / 15957

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Proteins
  • Osteonectin
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Mice, SCID
  • Mice
  • Membrane Glycoproteins
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 3