Integrin α6β4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer

Abstract

Background & Aims: Because alterations of integrin expression in cancers contribute to cancer cell biology, we analyzed the association between the potential for peritoneal dissemination and integrin expression. Methods: The dissemination potential of 10 human gastric cancer cell lines in mice with severe combined immunodeficiency (SCID) was compared with the expression of various integrins. The relationship between integrin expression and peritoneal dissemination was also investigated in surgically resected gastric cancer cases. Results: The level of integrin β4 subunit expression was inversely correlated with dissemination potential. Introduction of a full-length complementary DNA (cDNA) for β4 subunit into cancer cells showing negligible β4 subunit expression markedly suppressed peritoneal dissemination and inhibition of endogenous integrin α6β4 by introduction of a cytoplasmic domain-deleted β4 subunit cDNA into cells showing high expression of β4 subunit promoted peritoneal dissemination. Apoptosis, which was histologically evident in peritoneal nodules of SCID mice, was induced in the cells with high β4 subunit expression by attachment to laminin and stimulation with growth factors in vitro. An immunohistochemical study of specimens from 120 cases of primary gastric cancer showed that patients with β4 subunit–positive tumors exhibited peritoneal dissemination only infrequently ( P < 0.0001) and had a better outcome ( P < 0.01). Conclusions: These results indicate that integrin α6β4 is both a suppressor and a predictive marker for peritoneal dissemination in gastric cancer. GASTROENTEROLOGY 2000;118:497-506