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.
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.
Jensen
Søren Astrup
SA
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. soren.a.jensen@mail.tele.dk
Vainer
Ben
B
Bartels
Annette
A
Brünner
Nils
N
Sørensen
Jens Benn
JB
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
D009363:Neoplasm Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9