Back to Annual Meeting Program

Background. Methionine dependency is a feature unique to cancer cells, as demonstrated by their inability to grow in a methionine depleted environment even if the medium is supplemented with homocysteine, the immediate precursor of methionine. Treatment of disseminated gastric cancer is unsatisfactory and gastric tumors are frequently chemoresistant.
Aim. To investigate the effect of methionine deficiency in rodent models of gastric cancer dissemination.
Material and methods.
Moderate (MKN74) and poorly differentiated (MKN45 and KatoIII) human gastric cancer cell lines were used for these studies. To generate models of experimental peritoneal carcinomatosis (10 days) and xenograft model (65 days), these cell lines were injected intraperitoneally or subcutaneously, respectively, in NOD-SCID mice. For in vitro studies cells were growth in a complete medium with 10% bovine dyalized serum in a methionine free medium containing homocysteine(Met-Hcy+) or a medium containing methionine but depleted of homocytesine (Met+Hcy-).
Results. In the xenograft models induced by subcutaneous implantation of MNK45 and MNK74 cells, two cycles of methionine deficient diet (from day 20 to 27 and from day 34 to 41) reduced the tumor growth, measured on day 70, by 50 % (p<0.05 versus control diet). In the model of peritoneal carcinomatosis, induced by MNK45 cells injection, a cycle of methionine deficient diet for 10 days reduced peritoneal nodules from 27.0 ± 3.68 to 6.7 ± 0.8 (p<0.05). The intraperitoneal injection of MNK74 cells precultured for 3 days in a Met-Hcy+ medium almost abrogated peritoneal dissemination (p<0.05 versus Met+Hcy- medium precultured group).

Three-days in vitro culture In vitro of MKN45,MKN74 and KATOIII cells in a methionine deficient medium inhibited cell proliferation by 70-% and induced cell apoptosis. In addition, culturing cells in a methionine free medium reduced cell adhesion and migration significantly in comparison to Met+Hcy- medium (p<0.05). Finally, by microarray designed to analyze the methylation of promoter CpG-islets, we found that methionine deficiency reduced the promoter methilation of E-Cadherin and secreted frizzled-related protein 2 (SFRP-2) by 50%, two genes involved in the gastric cancer cell adhesion and proliferation, respectively.

Conclusions. Our experimental data suggest that a deficient methionine diet might affect neoplastic tumor growth by regulation of cell cycle, inducing apoptosis and decreasing cellular adhesion and migration.