Integrin alpha6beta4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer.
OBJECTIVE
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 beta4 subunit expression was inversely correlated with dissemination potential. Introduction of a full-length complementary DNA (cDNA) for beta4 subunit into cancer cells showing negligible beta4 subunit expression markedly suppressed peritoneal dissemination and inhibition of endogenous integrin alpha6beta4 by introduction of a cytoplasmic domain-deleted beta4 subunit cDNA into cells showing high expression of beta4 subunit promoted peritoneal dissemination. Apoptosis, which was histologically evident in peritoneal nodules of SCID mice, was induced in the cells with high beta4 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 beta4 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 alpha6beta4 is both a suppressor and a predictive marker for peritoneal dissemination in gastric cancer.
Ishii
Y
Y
Division of Pathology, National Cancer Center Research Institute, Tokyo, Japan.
Ochiai
A
A
Yamada
T
T
Akimoto
S
S
Yanagihara
K
K
Kitajima
M
M
Hirohashi
S
S
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers; D003593:Cytoplasm / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005544:Forecasting; D017353:Gene Deletion; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D010537:Peritoneum / Q000473:pathology*; D013274:Stomach Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000954:Antigens, Surface; D015415:Biomarkers; D018076:DNA, Complementary; D039161:Integrin alpha6beta4; D016023:Integrins