EMMPRIN-induced MMP-2 activation cascade in human cervical squamous cell carcinoma.
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.
Sier
Cornelis F M
CF
Department of Pathology, Leiden University Medical Center, The Netherlands. C.F.M.Sier@lumc.nl
Zuidwijk
Kim
K
Zijlmans
Henry J M A A
HJ
Hanemaaijer
Roeland
R
Mulder-Stapel
Adri A
AA
Prins
Frans A
FA
Dreef
Enno J
EJ
Kenter
Gemma G
GG
Fleuren
Gert Jan
GJ
Gorter
Arko
A
D051926:Basigin / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D011379:Prognosis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
C497886:BSG protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2