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Carcinogenesis Advance Access published online on February 10, 2006
Carcinogenesis, doi:10.1093/carcin/bgi351
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received November 22, 2005
Revised December 20, 2005
Accepted January 16, 2006

CARCINOGENESIS

Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma

Wei-Shu Wang 1, Po-Min Chen 1, Huann-Sheng Wang 2, Wen-Yih Liang 3, and Yeu Su 4 *

1 Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, Republic of China; National Yang-Ming University School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
2 National Yang-Ming University School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Division of Colorectal Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, Republic of China
3 National Yang-Ming University School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, Republic of China
4 Institute of Biopharmaceutical Science, Collage of Life Science, National Yang-Ming University, Taipei, Taiwan, Republic of China

* To whom correspondence should be addressed.
Yeu Su, E-mail: yeusu{at}ym.edu.tw


  Abstract

The ability of tumor cells to resist apoptosis triggered by immune cells results in their escape from immune surveillance of the host. A critical effector of apoptosis is the Fas/Fas ligand (FasL) system that mediates the tumoricidal effects of cytotoxic T-cells. Recently, in vitro cleavage of Fas expressed in various tumor cells by matrix metalloproteinase-7 (MMP-7) was demonstrated. In the present study, we first analyzed the influence of this metalloproteinase on Fas signaling in SW480, HCT-15, and HT-29 colorectal carcinoma (CRC) cells by assessing their responses to either an agonistic Fas antibody (CH11), or the FasL-bearing Jurkat cells after they were pretreated with MMP-7. Interestingly, both antibody- and Jurkat cell-induced apoptosis in three different CRC lines were significantly reduced by MMP-7 pretreatment. Additionally, immunohistochemical (IHC) staining was used to examine the expression levels of MMP-7 and Fas in tumor samples of 54 CRC patients. In agreement with our in vitro observation, the expression of MMP-7 in tumor tissues was inversely correlated with those of Fas (P<0.001, {chi}2 test). Moreover, shortened survival was found in patients with a higher MMP-7 and a lower Fas expression, respectively, in their tumor tissues (P<0.0001). Finally, by multivariate analysis, we discovered that MMP-7 (P=0.001) and Fas levels (P=0.036) were independent prognostic factors for CRC patients. These results suggest that Fas downregulation and a consequential increased resistance to FasL-triggered apoptosis resulted from upregulated MMP-7 in colorectal cancer cells could be a key mechanism for their escape from the immune surveillance, thereby predicting a poor survival in CRC patients.

Keywords: MMP-7; Fas; cleavage; immune evasion; colorectal carcinoma.
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