Abstract
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.