Membrane-type-1 matrix metalloproteinase, matrix metalloproteinase 2, and tissue inhibitor of matrix proteinase 2 in prostate cancer: identification of patients with poor prognosis by immunohistochemistry

Hum Pathol. 2008 May;39(5):731-9. doi: 10.1016/j.humpath.2007.09.021. Epub 2008 Mar 10.


Overexpression of the matrix metalloproteinase (MMP) 2 is associated with poor prognosis in many tumor types. Membrane-type-1 MMP (MMP14) activates MMP2 using pro-MMP2 specific inhibitor, tissue inhibitor of matrix proteinase 2 (TIMP2), as a receptor. We evaluated, by immunohistochemistry on 189 T3N0-2M0 prostate cancer (Pca) cases, the influence of MMP2, MMP14, and TIMP2 expression, individually and in association, on Pca disease-free survival (DFS). We evaluated marker expression separately in cancer, stromal, and benign epithelial (BE) cells according to a percentage scale (0%, <10%, 10%-50%, and >50%). Median follow-up was 4.61 years. In BE cells, there was an inverse relationship between initial prostate-specific antigen serum level and T3 stage with MMP14 expression (P = .003) and between pN stage and TIMP2 expression (P = .04). The most significant results with survival were obtained by dichotomizing the cases between those with less than 10% and at least 10% of cells expressing the marker, the latter category representing overexpression. TIMP2 overexpression in stromal cells was associated with a longer DFS with a hazard ratio of 0.573 (P = .02) for time to recurrence. MMP2 overexpression by BE cells correlated with a shorter DFS using a multivariate trend test (hazard ratio = 1.46, P = .02). Stromal cells expressing less than 10% TIMP2 and MMP2 overexpression was the only combination that was significantly associated with a shorter DFS (log-rank test, P = .0001). This study suggests that MMP14 is involved mostly in Pca implantation and that MMP2 and TIMP2 expression by reactive stromal cells might be used as predictors of DFS in T3N0-2M0 Pca.

MeSH terms

  • Adult
  • Aged
  • Canada / epidemiology
  • Disease-Free Survival
  • Epithelial Cells / metabolism
  • Humans
  • Immunohistochemistry
  • Male
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism*
  • Middle Aged
  • Prognosis
  • Prostatectomy
  • Prostatic Neoplasms / diagnosis*
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / therapy
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*


  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14