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

Aim: 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 = 0.9; 95% CI: 0.7-1.1; P = 0.2) or OS (HR = 0.8; 95% CI: 0.7-1.0; P = 0.07). Conclusion: 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. (C) 2010 Elsevier Ltd. All rights reserved.