In Silico analysis of Gastric carcinoma Serial Analysis of Gene Expression libraries reveals different profiles associated with ethnicity

Worldwide gastric carcinoma has marked geographical variations and worse outcome in patients from the West compared to the East. Although these differences has been explained by better diagnostic criteria, improved staging methods and more radical surgery, emerging evidence supports the concept that gene expression differences associated to ethnicity might contribute to this disparate outcome. Here, we collected datasets from 4 normal and 11 gastric carcinoma Serial Gene Expression Analysis (SAGE) libraries from two different ethnicities. All normal SAGE libraries as well as 7 tumor libraries were from the West and 4 tumor libraries were from the East. These datasets we compare by Correspondence Analysis and Support Tree analysis and specific differences in tags expression were identified by Significance Analysis for Microarray. Tags to gene assignments were performed by CGAP-SAGE Genie or TAGmapper. The analysis of global transcriptome shows a clear separation between normal and tumor libraries with 90 tags differentially expressed. A clear separation was also found between the West and the East tumor libraries with 54 tags differentially expressed. Tags to gene assignments identified 15 genes, 5 of them with significant higher expression in the West libraries in comparison to the East libraries. qRT-PCR in cell lines from west and east origin confirmed these differences. Interestingly, two of these genes have been associated to aggressiveness (COL1A1 and KLK10). In conclusion we found that in silico analysis of SAGE libraries from two different ethnicities reveal differences in gene expression profile. These expression differences might contribute to explain the disparate outcome between the West and the East

Russell Body Gastritis Concurrent with Eosinophilia: a case report

A 64-year-old male patient with a histological diagnosis of Russell body gastritis and with eosinophilic infiltrate in biopsy specimens is reported. The patient continued hemodialysis and pseudomembranous enteritis was contracted. Upper gastrointestinal endoscopy was performed due to poor appetite and blood eosinophilia. During endoscopy, a flare, swollen mucous membrane, and multiple verrucous erosions were noted in the gastric antrum. Biopsy and histopathological examination of gastric mucosa showed infiltration of plasma cells containing Russell bodies and eosinophils. Plasma cells containing Russell bodies were positive for CD138, immunoglobulin A (IgA) and kappa-light chain. Giemsa stained biopsy specimen revealed that the patient was negative for Helicobacter pylori. The patient was diagnosed with Russell body gastritis with eosinophilia. This is the first report of Russell body gastritis concurrent with eosinophilia. We discussed the possible correlation between the presence of plasma cells containing Russell bodies and gastric eosinophilia

Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice

Aim: Immunotherapies blocking the CD47-SIRP alpha pathway by targeting CD47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRP alpha exhibits relatively restricted tissue expression, SIRP alpha antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies (mAbs) against CD47 and/or SIRP alpha on gastroenterological tumors in syngeneic immunocompetent mouse models.Methods: We used in vitro and in vivo phagocytosis assays in C57B1J6J (B6) mice to investigate anti-CD47/SIRP alpha mAb effects on Hepal-6 and CMT93 originating from B6 mice. The influence of these mAbs on macrophage transmigration was also assessed. To investigate anti-SIRP alpha mAb therapy-induced inhibitory effects on sporadic colon cancer growth, we used a CDX2P9.5-NLS Cre:APC7FLOX (CPC-APC) mouse model.Results: Systemic anti-SIRP alpha mAb administration significantly increased Hepal-6 and CMT93 cell susceptibility to macrophage phagocytosis, both in vitro and in vivo. Conversely, similarly administered anti-CD47 mAb did not promote macrophage phagocytosis of target cells, whereas cells incubated with anti-CD47 mAb prior to inoculation were more susceptible to macrophage phagocytosis. In vitro cell migration assays revealed that binding with anti-CD47 mAb inhibited macrophage transmigration. Anti-SIRP alpha mAb treatment inhibited tumor progression in CPC-APC mice and significantly improved overall survival. Anti-CD47 mAb administration in vivo eliminated the phagocytosis-promoting CD47 blockade effect, probably by inhibiting macrophage transmigration/chemotaxis. In contrast, anti-SIRP alpha mAb exhibited enhanced macrophage phagocytic activity and marked anti-tumor effects against gastroenterological malignancies.Conclusion: SIRP alpha mAb augmentation of macrophage phagocytic activity may represent an effective treatment strategy for human gastrointestinal tumors.</p

Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium

Background: A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective: To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design: Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results: Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions: Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population

Synchronous squamous cell carcinoma of the breast and invasive lobular carcinoma

Letter to Edito

SAGE法で抽出した新規胃がん特異遺伝子の機能解析と診断・治療への展開

研究期間:平成17-18年度 ; 研究種目:基盤研究B ; 課題番号:17390104原著には既発表論文の別刷を含む