title: Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells--associations with histopathology and patients outcome.
abstract: OBJECTIVE
  To elucidate cellular features accountable for colorectal cancers' (CRC) capability to invade normal tissue and to metastasize, we investigated the level of the collagenase matrix metalloproteinase 9 (MMP-9) and its physiological inhibitor tissue inhibitor of metalloproteinases 1 (TIMP-1) in cancer cells and supporting stroma cells of CRC.
  
  
  METHODS
  Immunoreactivity of MMP-9 and TIMP-1 by carcinoma cells, lymphocytes and fibroblasts in archival specimens of paraffin-embedded primary tumours were retrospectively associated with outcome in 340 consecutive patients completely resected for CRC stages II-IV and subsequently treated with adjuvant 5-fluorouracil.
  
  
  RESULTS
  Expression of MMP-9 by carcinoma cells was demonstrated in 9% of specimens without association to recurrence free survival (RFS) (HR = 1.0; 95% CI: 0.6-1.8; P = 0.9) or overall survival (OS) (HR = 0.9; 95% CI: 0.5-1.6; P = 0.6). TIMP-1 expression by carcinoma cells, which appeared in 64% of the specimens, was inversely related with RFS (HR = 1.3; 95% CI: 0.9-1.8; P = 0.08) and OS (HR = 1.5; 95% CI: 1.1-2.1; P = 0.02). Expression of TIMP-1 by fibroblasts at the invasive border was directly related to RFS (HR = 0.7; 95% CI: 0.6-0.9; P = 0.02) and OS (HR = 0.7; 95% CI: 0.6-1.0; P = 0.05). Expression of MMP-9 by lymphocytes correlated significantly with the degree of peritumoural inflammation (P = 0.02) but not with RFS (HR = .9; 95% CI: 0.7-1.1; P = 0.2) or OS (HR = 0.8; 95% CI: 0.7-1.0; P = 0.07).
  
  
  CONCLUSIONS
  TIMP-1 in cancer cells is associated with poor prognosis independent of its function as inhibitor of MMP-9. MMP-9 and TIMP-1 are important mediators of the host-cancer cell interaction in the tumour microenvironment with significant influence on the histopathology and on prognosis of CRC.
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. soren.a.jensen@mail.tele.dk
authors.forename: Søren Astrup
authors.initials: SA
authors.lastname: Jensen
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.forename: Annette
authors.initials: A
authors.lastname: Bartels
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Jens Benn
authors.initials: JB
authors.lastname: Sørensen
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008854:Microscopy, Electron; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D009363:Neoplasm Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9