Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression.
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.
Hornebeck
William
W
Center National de la Recherche Scientifique (CNRS) UMR 6198, IFR53 Biomolecules, Faculties of Medicine and Sciences, Reims University, 51, rue Cognacq Jay, 51100 Reims, France. william.hornebeck@univ-reims.fr
Lambert
Elise
E
Petitfrère
Emmanuelle
E
Bernard
Philippe
P
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018450:Disease Progression; D004705:Endocytosis; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008954:Models, Biological; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D004792:Enzyme Precursors; D026502:LDL-Receptor Related Proteins; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9