Leiden University Scholarly Publications

Sier, Cornelis FM; Zuidwijk, Kim; Zijlmans, Henry JMAA; Hanemaaijer, Roeland; Mulder-Stapel, Adri A; Prins, Frans A; ... ; Gorter, Arko (2006)

EMMPRIN-induced MMP-2 activation cascade in human cervical squamous cell carcinoma

Article / Letter to editor

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 EMMPRIN. Positive immuno-staining 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, 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...Show moreTumor 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 EMMPRIN. Positive immuno-staining 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, 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 co-localization 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.Show less

cervix

cancer

matrix metalloproteinase

immunohistochemistry

MT1-MMP

TIMP-2

activity

All authors

Sier, Cornelis FM; Zuidwijk, Kim; Zijlmans, Henry JMAA; Hanemaaijer, Roeland; Mulder-Stapel, Adri A; Prins, Frans A; Dreef, Enno J; Kenter, Gemma G; Fleuren, Gert Jan; Gorter, Arko

Date

2006