Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression

Biochimie. Mar-Apr 2005;87(3-4):377-83. doi: 10.1016/j.biochi.2004.09.022.


Tissue inhibitor of metalloproteinase-1 (TIMP-1) is one representative of the natural matrix metalloproteinase (MMP) inhibitor family, encompassing four members. It inhibits all MMPs, except several MT-MMPs, and a disintegrin with a metalloproteinase domain (ADAM)-10 with Kis < nM. Unexpectedly, its upregulation was associated to poor clinical outcome for several cancer varieties. Such finding might be related to the growth-promoting and survival activities of TIMP-1 for normal and cancer cells. In most cases, such properties are MMP-independent and binding of TIMP-1 to an unknown receptor system can trigger JAK (or FAK)/PI3 kinase/Akt/bad-bclX2 (erythroid, myeloid, epithelial cell lines) or Ras/Raf1/FAK (osteosarcoma cell line) signaling pathways. The relationship between viral infection and TIMP-1 expression is here underlined. Thus, TIMP-1 might display a dual influence on tumor progression; either beneficial by inhibiting MMPs as MMP-9 and by impairing angiogenesis or detrimental by favoring cancer cells growth or survival. We consider that the proMMP-9/TIMP-1 balance is of critical importance in early events of tumor progression, and might show promise as diagnostic and prognostic marker of malignancy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Biomarkers, Tumor / metabolism
  • Disease Progression
  • Endocytosis
  • Enzyme Precursors / antagonists & inhibitors
  • Humans
  • LDL-Receptor Related Proteins / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Models, Biological
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Tissue Inhibitor of Metalloproteinase-1 / pharmacology
  • Tissue Inhibitor of Metalloproteinase-1 / physiology*


  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Enzyme Precursors
  • LDL-Receptor Related Proteins
  • Matrix Metalloproteinase Inhibitors
  • Tissue Inhibitor of Metalloproteinase-1
  • pro-matrix metalloproteinase 9
  • Matrix Metalloproteinase 9