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

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.

• Authors: Naohiko Koshikawa, Hiroto Mizushima, Tomoko Minegishi, Fuyuki Eguchi, Fusanori Yotsumoto, Kazuki Nabeshima, Shingo Miyamoto, Eisuke Mekada, Motoharu Seiki
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 1 Pg. 111-6 (Jan 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 20946474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Japanese Cancer Association.

Chemical References

• HBEGF protein, human
• Heparin-binding EGF-like Growth Factor
• Intercellular Signaling Peptides and Proteins
• Collagen
• MMP14 protein, human
• Matrix Metalloproteinase 14

Topics

• Cell Line, Tumor
• Collagen (metabolism)
• Female
• Heparin-binding EGF-like Growth Factor
• Humans
• Intercellular Signaling Peptides and Proteins (analysis, physiology)
• Matrix Metalloproteinase 14 (analysis, physiology)
• Neoplasm Invasiveness
• Ovarian Neoplasms (metabolism, pathology)