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

Jensen, Søren Astrup; Vainer, Ben; Bartels, Annette; Brünner, Nils; Sørensen, Jens Benn

doi:10.1016/j.ejca.2010.07.046

« Previous Next »European Journal of Cancer
Volume 46, Issue 18 , Pages 3233-3242, December 2010

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

Søren Astrup Jensen
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark
- Corresponding author: Address: Department of Oncology, 5073 Rigshospitalet, Copenhagen University Hospital, 9 Blegdamsvej, Copenhagen DK-2100, Denmark. Tel./fax: +45 4589 4478.
Ben Vainer
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Denmark
Annette Bartels
- Section of Pathobiology, Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Denmark
Nils Brünner
- Section of Pathobiology, Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Denmark
Jens Benn Sørensen
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark

Received 27 April 2010; received in revised form 26 July 2010; accepted 29 July 2010. published online 01 September 2010.

Abstract

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.

Keywords: Colonic neoplasms, Tissue inhibitor of metalloproteinases 1, Matrix metalloproteinase 9, Immunohistochemistry, Prognostic value of tests, Tumour markers, Biological, Survival rate, Treatment outcome, Disease-free survival, Fluorouracil