Epstein-Barr virus.

Helicobacter pylori is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong. H. pylori infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of H. pylori.

Pathogenesis of Helicobacter pylori Infection

Although gastric adenocarcinoma is associated with the presence of Helicobacter pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial-cell physiology. Understanding the host-microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.

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Helicobacter pylori and gastrointestinal tract adenocarcinomas

https://www.journal-of-hepatology.eu/article/S0168-8278(14)00526-1/pdf

Global epidemiology and genotype distribution of the hepatitis C virus infection

Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

Helicobacter pylori is classified by IARC/WHO as a definite human gastric carcinogen, despite "inadequate experimental evidence." To obtain direct evidence concerning this relationship, we investigated the histopathological findings of gastric mucosa using a model of H. pylori infection in Mongolian gerbils. The animals were challenged p.o. with H. pylori ATCC-43504 and sacrificed at 6, 12, and 18 months after inoculation for histological examination. All inoculated animals were infected with H. pylori. Severe infiltration of the lamina propria by polymorphonuclear and mononuclear cells appeared in the lesser curvature of the antrum, with an increase in epithelial cell proliferation, and the infiltration extended to the body. Atrophic gastritis and focal intestinal metaplasia also appeared in the lesser curvature of the antral mucosa at 6 months after inoculation. Intestinal metaplasia became severe, with dysplasia, after that. At 18 months after H. pylori inoculation, two of five infected animals showed three well-differentiated gastric cancers. The uninfected control animals showed no abnormal findings throughout the entire observation period. Here, it was confirmed that H. pylori infection alone causes gastric cancer in an animal model.

https://cancerres.aacrjournals.org/content/canres/58/19/4255.full.pdf

Development of Helicobacter pylori-induced Gastric Carcinoma in Mongolian Gerbils

C57BL/6 mice were orally immunized with five weekly doses of 2 mg, 200 μg, or 2 μg of Helicobacter pylori (Sydney strain) whole-cell sonicate combined with cholera toxin. One week after the last vaccination, mice were challenged with 5 × 107 CFU of live H. pylori three times at 2-day intervals. At 6 or 18 weeks after the challenge, mice were sacrificed and bacterial cultures and histological studies of the stomach were performed. Vaccination with 2 mg/session or 200 μg/session inhibited H. pylori colonization by 90 and 100%, respectively. These mice were considered protected. Lower levels of H. pylori-specific immunoglobulin A (IgA) were detected in fecal and saliva samples before challenge. However, a significant increase in IgA secretion in mucosal tissue and a higher labeling index for IgA-positive lumina of pyloric glands were noted in these mice in response to challenge and in a vaccine dose-dependent manner. In protected mice, however, severe gastritis characterized by marked infiltration of inflammation mononuclear cells was noted at 6 weeks after challenge, compared with the gastritis seen in unprotected mice or nonvaccinated, ordinarily infected mice. Marked expression of gamma interferon mRNA was detected in the stomach of all protected mice, and 50% of these mice expressed interleukin 4 (IL-4) or IL-5 mRNA. Our findings suggest that local secretory IgA antibody and severe postimmunization gastritis correlate well with protection of mice against H. pylori infection.

https://iai.asm.org/content/iai/67/5/2531.full.pdf

Local secretory immunoglobulin A and postimmunization gastritis correlate with protection against Helicobacter pylori infection after oral vaccination of mice.

Purpose: Pancreatic cancer has a poor prognosis and few effective therapies are available. The oncolytic effect of reovirus has been observed in cancer cells with an activated Ras signaling pathway, and pancreatic cancer may be a candidate target for reovirus because K-ras mutation is frequently found in pancreatic cancer. Experimental Design: In this study, we examined the feasibility of using reovirus (serotype 3) as an antihuman pancreatic cancer agent. Results: Reovirus was able to infect five human pancreatic cancer cell lines (Panc1, MIApaca-2, PK1, PK9, and BxPC3) in vitro . We also confirmed that the Ras activity in these cancer cell lines was elevated compared with that in the normal cell line and that susceptibility to reovirus was associated with the Ras activity of these cells. In a unilateral murine xenograft model using Panc1 and BxPC3 cell lines, each tumor growth was suppressed by intratumoral injection of reovirus. Furthermore, local injection of reovirus also had systemic antitumor effects in a bilateral xenograft model using Panc1 cell line. Immunohistochemical examination revealed that reovirus replication was observed within the tumor but not in surrounding normal tissue. Conclusions: These results suggest that reovirus can be considered for a novel therapy against pancreatic cancer.

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Oncolytic Viral Therapy for Human Pancreatic Cancer Cells by Reovirus

TNF-α inducing protein (Tipα) is secreted from Helicobacter pylori (H. pylori): it is a potent inducer of TNF-α and chemokine genes, mediated through NF-κB activation, and it also induces tumor-promoting activity in Bhas 42 cells. To investigate the carcinogenic mechanisms of H. pylori with Tipα, we first examined how Tipα acts on gastric epithelial cells. We found that fluorescent-Tipα specifically bound to, and then entered, the cells in a dose- and temperature-dependent manner, whereas deletion mutant of Tipα (del-Tipα), an inactive form, neither bound to nor entered the cells, suggesting the presence of a specific binding molecule. Mutagenesis analysis of Tipα revealed that a dimer formation of Tipα with a disulfide bond is required for both specific binding and induction of TNF-α gene expression. A confocal laser scanning microscope revealed some Tipα in the nuclei, but del-Tipα was not present, which indicated that an active form of Tipα can penetrate the nucleus and may be involved in the induction of TNF-α gene expression. Examination of Tipα production and secretion in 28 clinical isolates revealed that H. pylori obtained from gastric cancer patients secreted Tipα in significantly higher amounts than did H. pylori from patients with chronic gastritis, suggesting that Tipα is an essential factor in H. pylori inflammation and cancer microenvironment in the human stomach. Tipα is thus a new carcinogenic factor of H. pylori that can enter the nucleus through a specific binding molecule, and its mechanism of action is completely different from that of CagA. © 2008 Wiley-Liss, Inc.

TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells

Background: Helicobacter pylori infection is associated with gastroduodenal disease in humans. In this study we aimed to show this relationship directly in Mongolian gerbils. Methods: The animals were challenged orally with H. pylori and killed 1, 2, 3, and 6 months after inoculation for histologic and anti-H. pylori antibody titer examination. Results: The spiral bacteria were observed in the mucus and gastric pits of all infected animals. A severe infiltration of the lamina propria by polymorphonuclear and mononuclear cells was seen 1 month after H. pylori inoculation. The submucosa was infiltrated by mainly mononuclear cells with formation of lymphoid follicles. Erosion of the gastric mucosa appeared soon after inoculation, whereas gastric ulcers, gastritis cystica profunda, and atrophy with goblet cell metaplasia occurred between 3 and 6 months after inoculation. In the duodenal mucosa a mild inflammatory cell infiltration with ballooning and diminished number of duodenal glands was seen. The IgG anti...

Akira Nishizono

Papers

Development of Helicobacter pylori-induced Gastric Carcinoma in Mongolian Gerbils

Local secretory immunoglobulin A and postimmunization gastritis correlate with protection against Helicobacter pylori infection after oral vaccination of mice.

Oncolytic Viral Therapy for Human Pancreatic Cancer Cells by Reovirus

TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells

Gastric ulcer, atrophic gastritis, and intestinal metaplasia caused by Helicobacter pylori infection in Mongolian gerbils