TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis

Piera Valente, Gianfranco Fassina, Antonella Melchiori, Luciana Masiello, Michele Cilli, Angelo Vacca, Maurizio Onisto, Leonardo Santi, William G. Stetler-Stevenson, Adriana Albini

Research output: Contribution to journalArticlepeer-review

Abstract

The matrix metalloproteinase (MMP) inhibitor TIMP-2 has a high specificity for gelatinase A/MMP-2. An imbalance between gelatinase A and TIMP-2 in favor of enzymatic activity is linked to the degradation of the extracellular matrix (ECM) associated with several physiologic and pathologic events, including angiogenesis, invasion and metastasis. Since TIMPs are secreted molecules, they have the potential to be used for gene therapy of certain tumors. We transfected B16F10 murine melanoma cells, a highly invasive and metastatic cell line, with an expression vector harboring a cDNA encoding for human TIMP-2. The clones obtained were isolated and examined for TIMP-2 over-expression and changes in tumor cell phenotype. The amount of recombinant TIMP-2 produced correlated with a reduction in invasion. In an in vivo angiogenesis assay, TIMP-2-transfected clones showed reduced levels of blood vessel formation, and in vitro conditioned media from TIMP-2 transfectants showed diminished induction of endothelial cell migration and invasion. TIMP-2 over-expression limited tumor growth in vivo and neoangiogenesis when cells were injected subcutaneously in mice in the presence of Matrigel. However, TIMP-2 overexpressing clones were found to be more resistant to apoptosis than parental and control melanoma cells, while necrosis was increased. Our data confirm the role of TIMP-2 in the down- regulation of metastasis and angiogenesis but indicate a possible involvement in tumor cell survival.

Original languageEnglish
Pages (from-to)246-253
Number of pages8
JournalInternational Journal of Cancer
Volume75
Issue number2
DOIs
Publication statusPublished - Jan 19 1998

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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