Matrix metalloproteinase/tissue inhibitorsof matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers

Stephanie Curran, Sinclair Dundas, J. Buxton, M. F. Leeman, R. Ramsay, Graeme Ian Murray

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8229-8234
Number of pages5
JournalClinical Cancer Research
Volume10
DOIs
Publication statusPublished - Dec 2004

Keywords

  • METAL LOPROTEINASES
  • TISSUE INHIBITORS
  • MMP INHIBITION
  • TUMOR INVASION
  • EXPRESSION
  • ROLES
  • PROGRESSION
  • METASTASIS
  • THERAPY
  • STAGE

Cite this

Matrix metalloproteinase/tissue inhibitorsof matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers. / Curran, Stephanie; Dundas, Sinclair; Buxton, J.; Leeman, M. F.; Ramsay, R.; Murray, Graeme Ian.

In: Clinical Cancer Research, Vol. 10, 12.2004, p. 8229-8234.

Research output: Contribution to journalArticle

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AU - Curran, Stephanie

AU - Dundas, Sinclair

AU - Buxton, J.

AU - Leeman, M. F.

AU - Ramsay, R.

AU - Murray, Graeme Ian

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N2 - 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.

AB - 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.

KW - METAL LOPROTEINASES

KW - TISSUE INHIBITORS

KW - MMP INHIBITION

KW - TUMOR INVASION

KW - EXPRESSION

KW - ROLES

KW - PROGRESSION

KW - METASTASIS

KW - THERAPY

KW - STAGE

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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