Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma.
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; chi2-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 resulting 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.
Division of Medical Oncology, Department of Medicine. Division of Colorectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
Wei-Shu
WS
Wang
Po-Min
PM
Chen
Huann-Sheng
HS
Wang
Wen-Yih
WY
Liang
Yeu
Y
Su
D017209:Apoptosis; D002277:Carcinoma / Q000201:enzymology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism / Q000502:physiology*; D011379:Prognosis; D015398:Signal Transduction; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
D019014:fas Receptor; D020783:Matrix Metalloproteinase 7