Establishment of an orthotopic transplantable gastric cancer animal model for studying the immunological effects of new cancer therapeutic modules.
Tumor cell growth is influenced by the cellular microenvironment including the presence of immune cells and blood vessels. Currently, no transplantable gastric cancer syngeneic animal models exist; therefore, we set out to establish a mouse gastric carcinoma cell line, which was named mouse gastric carcinoma cell line 3I (MGCC3I), from forestomach carcinoma developed in benzo[a]pyrene-treated ICR mice. MGCC3I cells showed epithelial-like morphology, multinuclear giant cell formation, and retained an intestinal phenotype, which are similar to human gastric cancer carcinoma cells. The expression of gastric cancer markers MUC1, MUC2, and MUC5AC, and oncogenes c-myc, c-met, cyclin E1, and cancer stem cell marker CD44 was determined in MGCC3I cells. MGCC3I cells formed poorly differentiated stomach tumors following orthotopic implantation into the stomachs of syngeneic ICR mice. Histone deacetylase inhibitors are recognized as a new class of anticancer drugs. The immunological therapeutic effects of the histone deacetylase inhibitors sodium butyrate and valproic acid were evaluated in this new animal tumor model. Sodium butyrate inhibited MGCC3I stomach tumor formation in animal models. Increased tumor infiltration by CD8 T cells and neutrophils was observed in mice treated with sodium butyrate or valproic acid. Depletion of CD8 T cells significantly attenuated tumor regression mediated by histone deacetylase inhibitors, which is correlated with enhancement of the MHC class I pathway in MGCC3I cells. Taken together, we have successfully established an orthotopic transplantable gastric tumor animal model and demonstrated its usefulness in revealing the role of CD8 T cells in the therapeutic effects of sodium butyrate.
Shan
Yan-Shen
YS
Department of Surgery, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan, ROC.
Fang
Jung-Hua
JH
Lai
Ming-Derg
MD
Yen
Meng-Chi
MC
Lin
Pin-Wen
PW
Hsu
Hui-Ping
HP
Lin
Chian-Yuh
CY
Chen
Yi-Ling
YL
D000818:Animals; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D014635:Valproic Acid / Q000494:pharmacology
D002087:Butyrates; D019927:Cyclin E; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; C524626:Muc2 protein, mouse; D055262:Mucin-2; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C568314:cyclin E1, mouse; D014635:Valproic Acid