Epidermal growth factor (EGF) receptors (ErbB) and EGF family members represent promising targets for cancer therapy. Heparin-binding EGF (HB-EGF) is a member of the EGF family and is an important target for therapy in some types of human cancers. Processing of HB-EGF by proprotein convertases, and successively, by ADAM family proteases, generates a soluble growth factor that requires heparin as a cofactor. Although heparin potentiates HB-EGF activity in vitro, it is not clear how the

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... nding activity of HB-EGF is regulated. Here, we show that membrane type 1-matrix metalloproteinase (MT1-MMP; MMP14), a potent invasion-promoting protease, markedly enhances HB-EGF-dependent tumor formation in mice. MT1-MMP additionally cleaves HB-EGF and removes the NH 2 -terminal 20 amino acids that are important for binding heparin. Consequently, the processing of HB-EGF by MT1-MMP converts HB-EGF into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo. The ErbB family of receptors expressed in human gastric carcinoma cells play a role in mediating enhanced HB-EGF activity by MT1-MMP during invasive cell growth in collagen. Thus, we shed light on a new mechanism whereby HB-EGF activity is regulated that should be considered when designing HB-EGF-targeted cancer therapy. Cancer Res; 70 (14) ; 6093-103. Figure 4. HB-EGF and MT1-MMP expressed in human gastric carcinoma cells are supporting their invasive growth. A, expression of HB-EGF and MT1-MMP mRNAs in human gastric cancer cells was analyzed by RT-PCR. GAPDH mRNA was used as an internal control and cDNAs for MT1-MMP and HB-EGF were used as positive controls. B, inhibition of tumor cell growth by CRM197 (5 μg/mL) and MMI270 (5 μg/mL). These cells were cultured for 4 d in the presence/absence of the indicated inhibitors. The results represent the average of experiments performed in triplicate. The Student's t test was used for statistical analyses. C and D, comparison of cell growth activity (C) and morphology (D) of STKM-2 in collagen gels after incubation for 4 d. Koshikawa et al.