EMMPRIN (extracellular matrix metalloproteinase inducer) is a novel marker of poor outcome in serous ovarian carcinoma Authors
Cite this article as: Davidson, B., Goldberg, I., Berner, A. et al. Clin Exp Metastasis (2003) 20: 161. doi:10.1023/A:1022696012668 Abstract
EMMPRIN is a member of the immunoglobulin superfamily of adhesion molecules and has a role in the activation of several matrix metalloproteinases (MMP). The objective of this study was to investigate the expression of EMMPRIN in effusions, primary and metastatic tumors of serous ovarian carcinoma patients, as well as to evaluate its association with clinicopathologic parameters and with MMP and integrin expression. Eighty effusions and eighty-three solid lesions were evaluated for expression of EMMPRIN mRNA using
in situ hybridization (ISH). Protein expression was studied in 75 effusions and 55 biopsies using immunohistochemistry (IHC). EMMPRIN mRNA and protein were detected in carcinoma cells in 63/80 (79%) and 64/75 (85%) effusions, respectively. Expression was similar in peritoneal and pleural effusions. EMMPRIN was co-expressed with MMP-1 ( P<0.001), MMP-9 ( P=0.006) and the αv ( P=0.013) and β1 ( P=0.029) integrin subunits. In solid lesions, EMMPRIN localized most often to tumor cells (51/83 using ISH, 51/55 using IHC), but was also expressed in stromal and endothelial cells in approximately one third of the cases. EMMPRIN mRNA expression in tumor cells was most frequent in peritoneal metastases ( P=0.03). EMMPRIN expression in carcinoma cells of solid tumors showed an association with that of MMP-9 ( P=0.018), while labeling of stromal cells showed co-localization with the β1 integrin subunit ( P=0.043). In survival analysis, EMMPRIN protein expression in stromal cells of primary tumors ( P=0.012) and in endothelial cells of all solid tumors ( P=0.023) correlated with poor survival. In conclusion, EMMPRIN is a novel prognostic marker in ovarian carcinoma, and is co-expressed with other metastasis-associated molecules in this malignancy. The identical phenotype of carcinoma cells in pleural and peritoneal effusions provides further evidence to our theory that cells at these sites share similar genotypic and phenotypic profiles. EMMPRIN immunohistochemistry mRNA in situ hybridization metastasis ovarian carcinoma serous effusions survival
This revised version was published online in July 2006 with corrections to the Cover Date.
Liotta LA, Rao CN, Barsky SH. Tumor invasion and the extracellular matrix. Lab Invest 1983; 49: 636–49.
Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: An imbalance of positive and negative regulation. Cancer Res 1991; 51: 5054–9s.
Werb Z. ECM and cell surface proteolysis: Regulating cellular ecology. Cell 1997; 91: 439–42.
Prescott J, Troccoli N, Biswas C. Coordinate increase in collagenase mRNA and enzyme levels in human fibroblasts treated with the tumor cell factor, TCSF. Biochem Int 1989; 19: 257–66.
Ellis SM, Nabeshima K, Biswas C. Monoclonal antibody preparation and purification of a tumor cell collagenase-stimulatory factor. Cancer Res 1989; 49: 3385–91.
Nabeshima K, Lane WS, Biswas C. Partial sequencing and characterization of the tumor cell-derived collagenase stimulatory factor. Arch Biochem Biophys 1991; 285: 90–6.
Biswas C, Zhang Y, DeCastro R et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 1995; 55: 434–9.
Guo H, Majmudar G, Jensen TC et al. Characterization of the gene for human EMMPRIN, a tumor cell surface inducer of matrix metalloproteinases. Gene 1998; 220: 99–108.
Kataoka H, DeCastro R, Zucker S et al. Tumor cell-derived collagenase stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase. Cancer Res 1993; 53: 3154–8.
Lim M, Martinez T, Jablons J et al. Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. FEBS Lett 1998; 441: 88–92.
Guo H, Li R, Zucker S et al. EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface. Cancer Res 2000; 60: 888–91.
Berditchevski F, Chang S, Bodorova J et al. Generation of monoclonal antibodies to integrin-associated proteins. J Biol Chem 1997; 272: 29174–80.
DeCastro R, Zhang Y, Guo H et al. Human keratinocytes express EMMPRIN, an extracellular matrix metalloproteinase inducer. J Invest Dermatol 1996; 106: 1260–5.
van den Oord JJ, Paemen L, Opdennaker G et al. Expression of gelatinase B and the extracellular matrix metalloproteinase inducer EMMPRIN in benign and malignant pigment cell lesions of the skin. Am J Pathol 1997; 151: 665–70.
Caudroy S, Polette M, Tournier JM et al. Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase-2 in bronchopulmonary and breast lesions. J Histochem Cytochem 1999; 47: 1575–80.
Muraoka K, Nabeshima K, Murayama T et al. Enhanced expression of a tumor-cell-derived collagenase-stimulatory factor in urothelial carcinoma: its usefulness as a tumor marker for bladder cancers. Int J Cancer 1993; 55: 19–26.
Sameshima T, Nabeshima K, Toole BP et al. Expression of EMMPRIN (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas. Int J Cancer 2000; 88: 21–7.
Sameshima T, Nabeshima K, Toole BP et al. Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. Cancer Lett 2000; 157: 177–84.
Bedrossian CWM. Malignant Effusions: A Multimodal Approach to Cytologic Diagnosis. New York: Igaku-Shoin 1994.
Davidson B, Risberg B, Kristensen G et al. Detection of cancer cells in effusions from patients diagnosed with gynecological malignancies-evaluation of five epithelial markers. Virchows Arch 1999; 435: 43–9.
Young RH, Clement PB, Scully RE. Surface epithelial-stromal tumors. In Sternberg SS, Antonioli DA, Carter D, Mills SE, Oberman HA (eds): Diagnostic Surgical Pathology. Philadelphia: Lippincott Williams & Wilkins 1999; 2319–82.
Reed JA, Manahan LJ, Parks CS et al. Complete one-hour immunocytochemistry based on capillary action. Biotechniques 1992; 13: 434–43.
Davidson B, Goldberg I, Gotlieb WH et al. High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin Exp Metastasis 1999; 17: 799–808.
Davidson B, Reich R, Berner A et al. Ovarian carcinoma cells in serous effusions show altered MMP-2 and TIMP-2 mRNA levels. Eur J Cancer 2001; 37: 2040–9.
Davidson B, Goldberg I, Berner A et al. Expression of membrane-type 1,2 and 3 matrix metalloproteinases (MT1-MMP, MT2-MMP, MT3-MMP) mRNA in ovarian carcinoma cells in serous effusions. Am J Clin Pathol 2001; 115: 517–24.
Berner HS, Davidson B, Berner A et al. Expression of CD44 in effusions of patients diagnosed with serous ovarian carcinoma-diagnostic and prognostic implications. Clin Exp Metastasis 2000; 18: 197–202.
Davidson B, Berner A, Nesland JMet al. E-cadherin and
?-, ?-and ?-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J Pathol 2000; 192: 460–9.
Davidson B, Berner A, Nesland JM et al. Carbohydrate antigen expression in primary tumors, metastatic lesions, and serous effusions from patients diagnosed with epithelial ovarian carcinoma-evidence of up-regulated Tn and Sialyl Tn antigens expression in effusions. Hum Pathol 2000; 31: 1081–7.
Davidson B, Lazarovici P, Ezersky A et al. Expression levels of the NGF receptors TrkA and p75 in effusions and solid tumors of serous ovarian carcinoma patients. Clin Cancer Res 2001; 7: 3457–64.
Davidson B, Reich R, Kopolovic J et al. Interleukin-8 and vascular endothelial growth factor mRNA levels are down-regulated in ovarian carcinoma cells in serous effusions. Clin Exp Metastasis 2002; 19: 135–44.
Davidson B, Risberg B, Goldberg I et al. Ets-1 mRNA expression in effusions of serous ovarian carcinoma patients is a marker of poor outcome. Am J Surg Pathol 2001; 25: 1493–500.
Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 2001; 264: 169–84.
Davidson B, Risberg B, Berner A et al. Expression of cell cycle proteins in ovarian carcinoma cells in serous effusions-biological and prognostic implications. Gynecol Oncol 2001; 83: 249–56.
Davidson B, Reich R, Goldberg I et al. Ets-1 mRNA expression is a novel marker of poor survival in ovarian carcinoma. Clin Cancer Res 2001; 7: 551–7.
Goldberg I, Davidson B, Reich R et al.
V integrin is a novel marker of poor prognosis in advanced-stage ovarian carcinoma. Clin Cancer Res, 2001; 7: 4073–9.
PubMed Copyright information
© Kluwer Academic Publishers 2003