1. ^*Department of Laboratory Medicine and Pathology, Minneapolis, Minnesota, USA
2. ^†University of Minnesota Cancer Center, Minneapolis, Minnesota, USA
3. ^‡Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA

Correspondence: Joji Iida, Ph.D., Laboratory Medicine and Pathology, Mail code Box609, University of Minnesota, 420 Delaware Street, Minneapolis, MN 55455, USA. Email: iidax002@tc.umn.edu

Received 12 May 2003; Revised 4 August 2003; Accepted 28 August 2003; Published online 5 January 2004.

Abstract

Membrane type-I metalloproteinase (MT1-MMP) is a transmembrane metalloproteinase that is critical for tumor cell invasion. MT1-MMP can degrade extracellular matrix (ECM) proteins directly and/or indirectly by activating soluble MMPs such as pro-MMP-2. Although MT1-MMP is upregulated in malignant melanoma, the biological consequences of elevated MT1-MMP expression for tumor progression are not enirely understood. In the current study, we have utilized the Bowes melanoma line for evaluating MT1-MMP in invasion and growth. Our studies extend the earlier observations to demonstrate that MT1-MMP expression in Bowes melanoma cells promotes selective invasion into matrigel but not matrices consisting of type-I collagen. Furthermore, MT1-MMP expressing melanoma cells exhibit increased migration in response to laminin 1 but not to type-I or type-IV collagen. MT1-MMP expression results in enhanced 3 dimensional growth in agarose gels and in long-term cultures within matrigel. The hydroxymate inhibitor BB94 inhibits MT1-MMP enhanced invasion and growth in 3 dimensional culture systems, but had no effect on increased motility. We demonstrated that MT1-MMP expression significantly facilitated tumorigenicity and growth by intradermal injection. The results suggest a more general role for elevated MT1-MMP in promoting both the selective invasion and increased growth of malignant melanoma in vivo.