Proteolytic activation of heparin‐binding EGF‐like growth factor by membrane‐type matrix metalloproteinase‐1 in ovarian carcinoma cells

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Abstract
Increased expression of heparin‐binding EGF‐like growth factor (HB‐EGF) and membrane‐type matrix metalloproteinase‐1 (MT1‐MMP) is frequently associated with various types of malignant tumor. HB EGF‐like growth factor has been reported to promote the malignant progression of ovarian carcinoma. Based on this finding, inhibition of HB‐EGF activity with CRM197 is now under phase I clinical evaluation. On the other hand, MT1‐MMP expressed in ovarian carcinoma cells is thought to promote invasion and growth of tumor cells by degrading the extracellular matrix. However, we recently demonstrated that co‐expression of MT1‐MMP and HB‐EGF in gastric carcinoma cells leads to cleavage of HB‐EGF within its N‐terminal heparin‐binding region, converting it into a potent heparin‐independent growth factor. In this study, we evaluated the importance of regulation of HB‐EGF by MT1‐MMP in clinical samples of ovarian carcinoma. We detected co‐expression of HB‐EGF and MT1‐MMP in clear cell ovarian carcinoma tissues, particularly at the invasion front and in tumor cells that had disseminated into the ascites, whereas HB‐EGF alone was expressed in non‐invasive borderline ovarian tumor tissue. Furthermore, a soluble HB‐EGF fragment that corresponds to that processed by MT1‐MMP was detected in malignant ascites obtained from patients with metastatic ovarian carcinoma. Ovarian carcinoma cells that express MT1‐MMP and HB‐EGF exhibited enhanced cell growth in a 3D‐collagen matrix and anchorage‐independent growth in suspension. These results indicate that MT1‐MMP co‐expressed with HB‐EGF in ovarian carcinoma cells potentiates the activity of HB‐EGF to promote invasive tumor growth and spreading in vivo. (Cancer Sci 2011; 102: 111–116)

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