1. ¹Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
2. ²Department of Cell Biology, The Scripps Research Institute, La Jolla, California

Correspondence: Dr. Gianluigi Giannelli, Dipartimento di Clinica Medica, Immunologia e Malattie Infettive, Clinica Medica II. Policlinico, Piazza G. Cesare 11, 70124, Bari, Italy. E-mail: g.giannelli@intmed.uniba.it

Received 26 January 2001.

Abstract

Hepatocellular carcinoma (HCC) is the most frequent malignant tumor of the liver; prognosis depends on the tendency to metastasize. Cancer cell invasion is regulated by proteolytic remodeling of extracellular matrix components and by integrin expression. We have shown that matrix metalloproteinase-2 (MMP-2) and membrane-type–1 matrix metalloproteinase (MT1-MMP) cleave Laminin-5 (Ln-5), stimulating cell migration. Here we report that all HCC cells express MT1-MMP, migrate on Ln-1 and Collagen IV, whereas only HCC cells that express 31 integrin secrete detectable levels of gelatinases, migrate on Ln-5, and invade through a reconstituted basement membrane (BM). Migration on Ln-5 is blocked by BB-94, an MMP inhibitor, and by MIG1, a monoclonal antibody that hinders migration on MMP-2–cleaved Ln-5. Invasion through a reconstituted BM is also inhibited by BB-94. HCC 31-negative cells migrate on Ln-1 and Collagen IV, but not on Ln-5, and do not invade through a reconstituted BM, although they express MT1-MMP. Anti-31 blocking antibodies inhibit gelatinase activation, cell motility, and cell invasion through Matrigel. In vivo, 31 integrin and Ln-5 are expressed in HCC tissue but not in normal liver. In conclusion, our data suggest that both 31 integrin and gelatinase activity are required for HCC migration and invasion.