Matrix Metalloproteinase/Tissue Inhibitors of Matrix Metalloproteinase Phenotype Identifies Poor Prognosis Colorectal Cancers
2004
Purpose: The matrix metalloproteinases (MMPs) are
a family of proteolytic enzymes involved in tumor invasion; several
individual members of which have been implicated in tumor prognosis.
These enzymes and their physiologic inhibitors, the tissue inhibitors
of matrix metalloproteinases (TIMPs), act in a coordinated manner to
form an integrated system. Therefore, to understand their role in tumor
invasion, it is necessary to evaluate them collectively. Experimental Design: In this study all of the
major members of the matrix metalloproteinase (MMP-1, MMP-2, MMP-3,
MMP-7, MMP-9, MMP-13, MT1-MMP and MT2-MMP)/tissue inhibitor of matrix
metalloproteinase (TIMP-1, TIMP-2, and TIMP-3) system have been
investigated by immunohistochemistry in a series ( n = 90) of stage III (Dukes’ C) colorectal cancers. An
immunohistochemical score based on the intensity of immunoreactivity
and proportion of immunoreactive cells was established for each MMP and
TIMP. Results: The MMP/TIMP profile defined by hierarchical
cluster analysis of the immunohistochemical score identifies a distinct
group of colorectal cancers with poor prognosis (log-rank test, 12.22,
P = 0.0005). The median survival time of patients
in this survival group was 18 months compared with a median survival of
49 months in the “good” survival group. Multivariate analysis
showed that this profile was independently the most significant
prognostic factor ( P = 0.001). Conclusions: This study has identified that the MMP/TIMP
profile is an independent indicator of poor prognosis in colorectal
cancer.
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