A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.

Xenotransplantation of human cancers into immunodeficient mice is a very useful approach for studying human tumor biology. However, the occasional occurrence of lymphomagenesis in some mice can spoil the model and must be investigated in detail. We found that a high percentage (32.5%, 26/80) of cancer patient-derived xenografts (PDXs) resembled lymphoma in NOD/SCID mice. Of the 26 xenografts, 23 were human-derived expressing human CD45 (hCD45+) and proved to be of the B-cell subtype (CD3-/CD20+), and they were all positive for Epstein - Barr virus (EBV). The remaining 3 xenografts proved to be mouse-derived for both hCD45- and negative amplification of a human gene. The most interesting finding is that gastric cancer had much higher rates (24/126, 19.0%) of lymphoma formation in the PDX model than did colorectal cancer (1/43, 2.3%). Statistical analysis revealed that cancer type and inflammation in the parent tumor are significantly associated with lymphomagenesis. Further validation discovered lymphomagenesis by inoculating only gastritis mucosa. Therefore, our findings suggest that it is necessary to take precautions when directly xenografting cancer tissues with remarkable baseline inflammation, such as gastric cancer into immunodeficient NOD/SCID strains. Further, the established xenograft models should be validated by both leukocyte markers and human gene signatures.

MiR-130a-3p was found to play tumor suppressor role in most human cancers, except for gastric cancer. However, in this study, we demonstrated that miR-130a-3p was significantly down-regulated in gastric carcinoma (GC) tissues compared with adjacent non-neoplastic tissues, and decreased miR-130a-3p expression was associated with shorter overall survival (OS) and was an independent prognostic factor for OS in GC patients. Over-expression of miR-130a-3p remarkably inhibited not only GC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, but also tumorigenesis and lung metastasis in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Conversely, inhibition of miR-130a-3p resulted in opposite phenotype changes in GC cells. Furthermore, TBL1XR1 was identified as a direct target of miR-130a-3p, and reintroduction of TBL1XR1 into miR-130a-3p-transfected MGC-803 cells reversed the inhibitory effects of miR-130a-3p on GC cell migration, invasion and EMT. Taken together, our data suggested that miR-130a-3p suppressed aggressive phenotype of GC cells partially by direct targeting and decreasing TBL1XR1 and subsequent EMT process.

Our results revealed that copy number gains in MYC and TNFRSF11B located at 8q24 are associated with survival in GC, particularly noncardia GC.

BackgroundS100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression.MethodsS100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated.ResultsS100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells.ConclusionsOur results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis.