Patients with advanced gastric
carcinoma, especially peritoneal dissemination, have a poor prognosis even after any treatment.
Chemokines are now known to play an important role in
cancer growth and
metastasis. We recently reported that the
chemokine CXCL12 plays an important role in the development of
peritoneal carcinomatosis from gastric
carcinoma. In this study, we investigated signalling pathway involved in the
peritoneal carcinomatosis induced by
chemokine CXCL12. Akt was rapidly and strongly phosphorylated by
chemokine CXCL12. CXCL12 also induced the activation of
p70S6K (S6K) and
eukaryotic initiation factor 4E binding protein 1 (4E-BP1) included in
mammalian target of rapamycin (mTOR) pathways which are located downstream of Akt, resulting in enhancements of metastatic properties such as
MMP production, cell migration and cell growth in peritoneal disseminated
gastric cancer, NUGC4 cells. Furthermore, mTOR inhibitor
rapamycin not only drastically inhibited migration and
MMP production, but also induced type II programmed cell death, autophagic cell death. In the present study, we have shown for the first time that the mTOR pathway plays a central role in the development of
peritoneal carcinomatosis, and blocking this pathway induces autophagic cell death in disseminated
gastric cancer. Therefore, blocking on the CXCR4/mTOR signalling pathway may be useful for the future development of a more effective therapeutic strategy for
gastric cancer involved in peritoneal dissemination.