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author:("stoic, Calin")
1.  T-bet Knockout Prevents Helicobacter felis-Induced Gastric Cancer1 
Helicobacter infection is the primary risk factor for gastric cancer, with the cytokine environment within the gastric mucosa the strongest predictor of disease risk. Elevated TNF-α, IL-1β, and low IL-10 are associated with the highest risk. In this study, we used C57BL/6 mice to identify T-bet as a central regulator of the cytokine environment during Helicobacter felis infection. We infected male and female C57BL/6 and C57BL/6-T-bet knockout (KO) liter mates with H. felis and examined the bacterial colonization, immune response, and mucosal damage at varying time points. T-bet KO mice maintained infection for 15 mo at similar levels to wild-type mice. Infection and immune response did not differ between male and female mice. Despite sustained infection, T-bet KO mice respond with a blunted Th1 response associated with preservation of parietal and chief cells and protection from the development of gastric cancer. Unexpectedly, T-bet KO mice develop a gastric environment that would not be expected based on the phenotype of T-bet KO CD4 cells alone. T-bet KO mice respond to H. felis infection with a markedly blunted IL-1β and TNF-α and elevated IL-10 levels. Activity of this one master regulator modulates the expression of the key gastric mucosal cytokines associated with gastric cancer and may be a target for therapy to restore immune balance clinically in patients at risk for gastric cancer.
doi:10.4049/jimmunol.0900511
PMCID: PMC3966469  PMID: 19535625
2.  Mesenchymal Stem Cells Utilize CXCR4–SDF-1 Signaling for Acute, but Not Chronic, Trafficking to Gastric Mucosal Inflammation 
Digestive Diseases and Sciences  2013;58(9):2466-2477.
Background
Helicobacter infection is the main risk factor in developing gastric cancer. Mesenchymal stem cells (MSCs) are non-hematopoietic stromal cells, which are able to differentiate into different cell lineages. MSC contribute to cancer development by forming the tumor directly, contributing to the microenvironment, or by promoting angiogenesis and metastasis. CXCR4/SDF-1 axis is used by MSC in trafficking, homing, and engraftment at chronic inflammation sites, and plays an important role in tumorigenesis.
Aim
To determine if CXCR4 receptor has a role in MSC contribution to the development of Helicobacter-mediated gastric cancer.
Methods
SDF-1 and CXCR4 expression in mouse gastric mucosa in the setting of acute and chronic inflammation was measured using RT-PCR. Mouse culture-adapted MSC express CXCR4. Wild-type C57BL/6 mice infected with Helicobacter felis for 6 months or controls were given IV injections of CXCR4 knock-down MSC. Animals were followed for another 4 months. Homing of MSC in the stomach was quantified using RT-PCR. MSC differentiation into gastric epithelia lineages was analyzed using immunohistochemistry and fluorescent in situ hybridization.
Results
CXCR4 and SDF-1 are both upregulated in the settings of Helicobacter-induced chronic gastric inflammation. CXCR4 is fully required for homing of MSC to the stomach in acute gastric inflammation, but only partially in Helicobacter-induced gastric cancer. MSC lead to gastric intraepithelial neoplasia as early as 10 months of Helicobacter infection.
Conclusions
Our results show that MSC have a tumorigenic effect by promoting an accelerated form of gastric cancer in mice. The engraftment of MSC in chronic inflammation is only partially CXCR4-dependent.
doi:10.1007/s10620-013-2782-y
PMCID: PMC3766519  PMID: 23873382
Gastric cancer; Helicobacter; Mesenchymal stem cells; CXCR4; SDF-1
3.  Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver 
Gastroenterology  2009;137(3):934-944.e4.
Background and aim
Analysis of clinical colon cancer specimens show alterations in the CD95 (Fas Ag/Fas L) pathway as tumors progress from local to metastatic disease, suggesting this pathway may play a role in invasive behavior of colon cancer. However, direct causality between these alterations and clinical disease progression has not been shown.
Methods
Surgically resected metastatic colon cancer samples were evaluated for Fas Ag/L and apoptosis. Alterations in the Fas signaling pathway found in human samples was recreated through a series of staged transfection experiments in the MC38 mouse colon cancer cell line and the effects on growth tested in vitro, and in vivo.
Results
Expression of FLICE like inhibitory protein (FLIP) confers apoptosis resistance, increasing the incidence of primary tumors through a survival advantage by avoiding apoptosis and inducing Fas mediated proliferation. Co-expression of Fas L enables colon cancer cells to metastasize to the liver from local tumors as well as from intravenous injection of cells. MC38-FasL/FLIP colon cancer cells induce apoptosis in hepatocytes via activation of type 2 Fas Ag signaling, thus creating a niche conducive to tumor growth and fueling their own growth via Fas proliferative signaling.
Conclusion
Alterations in the Fas Ag pathway which inhibit apoptosis and increase Fas mediate proliferation directly increases local colon cancer growth and enhances metastasis to the liver. Delineating points in the pathway responsible for growth and metastasis will offer targets which may be exploited for therapy.
doi:10.1053/j.gastro.2009.06.004
PMCID: PMC2763556  PMID: 19524576
4.  Green tea inhibits Helicobacter growth in vivo and in vitro 
Helicobacter infection, one of the most common bacterial infections in man worldwide, is a type 1 carcinogen and the most important risk factor for gastric cancer. Helicobacter pylori bacterial factors, components of the host genetics and immune response, dietary cofactors and decreased acid secretion resulting in bacterial overgrowth are all considered important factors for induction of gastric cancer. Components found in green tea have been shown to inhibit bacterial growth, including the growth of Helicobacter spp. In this study, we assessed the bactericidal and/or bacteriostatic effect of green tea against Helicobacter felis and H. pylori in vitro and evaluated the effects of green tea on the development of Helicobacter-induced gastritis in an animal model. Our data clearly demonstrate profound growth effects of green tea against Helicobacter and, importantly, demonstrate that green tea consumption can prevent gastric mucosal inflammation if ingested prior to exposure to Helicobacter infection. Research in the area of natural food compounds and their effects on various disease states has gained increased acceptance in the past several years. Components within natural remedies such as green tea could be further used for prevention and treatment of Helicobacter-induced gastritis in humans.
doi:10.1016/j.ijantimicag.2008.10.032
PMCID: PMC2694061  PMID: 19157800
Helicobacter felis; Helicobacter pylori; Gastric cancer; Green tea; Catechins; Diet
5.  Stem cells and cancer: Evidence for bone marrow stem cells in epithelial cancers 
Cancer commonly arises at the sites of chronic inflammation and infection. Although this association has long been recognized, the reason has remained unclear. Within the gastrointestinal tract, there are many examples of inflammatory conditions associated with cancer, and these include reflux disease and Barrett’s adenocarcinoma of the esophagus, Helicobacter infection and gastric cancer, inflammatory bowel disease and colorectal cancer and viral hepatitis leading to hepatocellular carcinoma. There are several mechanisms by which chronic inflammation has been postulated to lead to cancer which includes enhanced proliferation in an endless attempt to heal damage, the presence of a persistent inflammatory environment creating a pro-carcinogenic environment and more recently a role for engraftment of circulating marrow-derived stem cells which may contribute to the stromal components of the tumor as well as the tumor mass itself. Here we review the recent advances in our understanding of the contributions of circulating bone marrow-derived stem cells to the formation of tumors in animal models as well as in human beings.
doi:10.3748/wjg.v12.i3.363
PMCID: PMC4066053  PMID: 16489634
Epithelial cancer; Stem cells
6.  Major Histocompatibility Complex Class II Inhibits Fas Antigen-Mediated Gastric Mucosal Cell Apoptosis through Actin-Dependent Inhibition of Receptor Aggregation  
Infection and Immunity  2005;73(10):6311-6321.
Escape from normal apoptotic controls is thought to be essential for the development of cancer. During Helicobacter pylori infection, the leading cause of gastric cancer, activation of the Fas antigen (Fas Ag) apoptotic pathway is responsible for early atrophy and tissue loss. As disease progresses, metaplastic and dysplastic glands arise which express Fas Ag but are resistant to apoptosis and are believed to be the precursor cells for adenocarcinoma. In this report, we show that one mechanism of acquired Fas resistance is inhibition of receptor aggregation via a major histocompatibility complex class II (MHCII)-mediated, actin-dependent mechanism. For these studies we used the well-described C57BL/6 mouse model of Helicobacter pylori and Helicobacter felis infection. Under normal conditions, Fas Ag is expressed at low levels, and MHCII expression on gastric mucosal cells is negligible. With infection and inflammation, both receptors are upregulated, and 6.1% of gastric mucosal cells express MHCII in combination with Fas Ag. Using the rat gastric mucosal cell line RGM-1 transfected with murine Fas Ag and MHCIIαβ chains, we demonstrate that MHCII prevents Fas receptor aggregation and inhibits Fas-mediated signaling through its effects on the actin cytoskeleton. Depolymerization of actin with cytochalasin D allows receptors to aggregate and restores Fas sensitivity. These findings offer one mechanism by which gastric mucosal cells acquire Fas resistance.
doi:10.1128/IAI.73.10.6311-6321.2005
PMCID: PMC1230908  PMID: 16177302

Results 1-6 (6)