TY - JOUR
T1 - Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer
AU - Lengyel, Ernst
AU - Schmalfeldt, Barbara
AU - Konik, Elisabeth
AU - Späthe, Kerstin
AU - Härting, Kathrin
AU - Fenn, Anke
AU - Berger, Ursula
AU - Fridman, Rafael
AU - Schmitt, Manfred
AU - Prechtel, Dieter
AU - Kuhn, Walther
N1 - Funding Information:
We are grateful to Dr. K. Iwata and Dr. R. Nemori (Fuji Chemicals Industries, Japan) for providing us the gelatin films. We thank Dr. H. Allgayer and R. Manson, M.A., for their critical appraisal of the manuscript and Prof. Dr. K. Ulm for helpful discussions. The work would not have been possible without the contribution of Juliane Schäfer in the statistical analysis. This work was supported by grants from the Deutsche Krebshilfe/Dr. Mildred Scheel Stiftung (10-1197 and 10-1637 to E.L., B.S., and W.K.), the Medical Faculty of the Technische Universität München (KKF 8756156 to E.L. and M.S.), and the National Cancer Institute (CA-61986 to R.F.).
PY - 2001
Y1 - 2001
N2 - Objective. Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. Methods. MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. Results were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/μg protein in benign ovarian tissues and 4.82 U/μg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. Conclusions. Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.
AB - Objective. Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. Methods. MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. Results were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/μg protein in benign ovarian tissues and 4.82 U/μg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. Conclusions. Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.
KW - Matrix metalloproteinase 2
KW - Matrix metalloproteinase 9
KW - Ovarian cancer
KW - Prognosis
KW - Zymography
UR - http://www.scopus.com/inward/record.url?scp=0034909346&partnerID=8YFLogxK
U2 - 10.1006/gyno.2001.6243
DO - 10.1006/gyno.2001.6243
M3 - Article
AN - SCOPUS:0034909346
SN - 0090-8258
VL - 82
SP - 291
EP - 298
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 2
ER -
