EMMPRIN-induced MMP-2 activation cascade in human cervical squamous cell carcinoma
article
Tumor progression and recurrence of cervical cancer is associated with upregulation of matrix metalloproteinase 2 (MMP-2). We evaluated the location, origin and activity of MMP-2 in cervical squamous cell carcinomas in comparison with MT1-MMP (MMP-14), TIMP-2 and extracellular matrix metalloproteinase inducer (EMMPRIN). Positive immunostaining for MMP-2 in malignant cells was detected in 83% of the patients. Two patterns of tumor cell MMP-2 staining were observed: either homogenous in all tumor cells or confined to the cells neighboring the stroma (tumor-border staining pattern, TBS). Fluorescence in situ zymography showed active MMP-2 mainly around tumor nodules displaying TBS. The MMP-2 staining of TBS tumors correlated significantly with the presence of TIMP-2 and MT1-MMP, proteins involved in docking MMP-2 to the cell surface and essential for MMP-2 activation. In situ mRNA hybridization in TBS tumors demonstrated more abundant presence of MMP-2 mRNA in neighboring myofibroblasts than in the adjacent tumor cells. Moreover, the TBS MMP-2 pattern correlated with the presence of EMMPRIN (p = 0.023), suggesting that tumor cells induce MMP-2 production in nearby stromal cells. This pro-MMP-2 could subsequently be activated on tumor cells via the presence of MT1-MMP and TIMP-2. The biological relevance of this locally activated MMP-2 was underscored by the observation that only the TBS pattern of MMP-2 significantly correlated with decreased survival. In conclusion, the colocalization of EMMPRIN, MT1-MMP and TIMP-2 in human cervical carcinomas seems to be involved in a specific distribution pattern of tumor cell bound MMP-2, which is related with local proteolytic activity and therefore might be associated with worse prognosis of the patients. © 2006 Wiley-Liss, Inc. Chemicals / CAS: gelatinase A, 146480-35-5; tissue inhibitor of metalloproteinase 2, 124861-55-8; Antigens, CD147, 136894-56-9; BSG protein, human; Matrix Metalloproteinase 2, EC 3.4.24.24; Matrix Metalloproteinases, EC 3.4.24.-; Matrix Metalloproteinases, Membrane-Associated, EC 3.4.24.-; Tissue Inhibitor of Metalloproteinase-2, 127497-59-0
Topics
Biomedical ResearchCervix cancerEMMPRINImmunohistochemistryIn situ zymographyMatrix metalloproteinaseMT1-MMPTIMP-2CD147 antigengelatinase Amatrix metalloproteinase 14messenger RNAtissue inhibitor of metalloproteinase 2cancer recurrencehuman tissueimmunofluorescenceimmunohistochemistryprotein degradationprotein localizationRNA hybridizationsquamous cell carcinomastroma celltumor growthuterine cervix carcinomazymographyAntigens, CD147Carcinoma, Squamous CellEnzyme ActivationFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryIn Situ HybridizationMatrix Metalloproteinase 2Matrix MetalloproteinasesMatrix Metalloproteinases, Membrane-AssociatedPrognosisTissue Inhibitor of Metalloproteinase-2Uterine Cervical Neoplasms
TNO Identifier
239324
ISSN
00207136
Source
International Journal of Cancer, 118(12), pp. 2991-2998.
Pages
2991-2998
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