Gastric cancers with liver
metastasis are fatal diseases with rapid progression and poor patient outcome. To date, however, the molecular basis of their growth and
metastasis remains essentially unknown, largely because of the presence of few available
gastric cancer cell lines established from liver
metastasis. In the present study, we developed two novel cultured cell lines (designated GLM-1 and GLM-2) and one transplantable line in nude mice (designated GLM-3) derived from liver
metastasis of
gastric cancer patients. These GLM cell lines share unique biological features such as differentiation, growth and
metastasis. They form moderately differentiated
tumors with CD10 positive and MUC2 negative intestinal absorptive phenotype when injected into nude mice. Their growth is stimulated by
EGF and
TGF-alpha in vitro like other
gastric cancer cell lines. However, GLM cells differ from conventional
gastric cancer cell lines in their high apoptotic rate, even in the absence of apoptosis inducing stimuli as revealed by Caspase3/7 assay and the TUNEL method. This apoptosis is further enhanced by
phosphatidylinositol 3-kinase (PI3K) inhibitor (
LY294002), but not by MEK1/2 inhibitor (
U0126), indicating the strong dependency of their survival on PI3K/Akt pathway rather than MAPK pathway, the major downstream signaling pathways of EGFR. GLM-1 cells can metastasize to the liver after intrasplenic injection, and GLM-3 cells have spontaneous lung metastatic potential after subcutaneous
transplantation, respectively. These results indicate that the GLM series are the first cell lines reflecting the intestinal-type differentiated
adenocarcinoma, a major subtype of
gastric cancer with liver
metastasis. Therefore, they would be excellent models for understanding the mechanism of metastatic growth and the development of a new molecular targeting
therapy for
gastric cancer with liver
metastasis.