Nature meets nurture: molecular genetics of gastric cancer

The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest findings as well as to look at the larger picture in terms of how to tackle the problem of solving this multi-piece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inflammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diffuse gastric cancer is highlighted, and finally the ever growing discipline of SNP analysis (including IL1B) is discussed

Helicobacter and gastric cancer disease mechanisms: host response and disease susceptibility

Helicobacter infection is the single most common cause of gastric cancer worldwide. Although infection prevention and eradication of established infection offer the potential for cure, these strategies are neither feasible nor practical for widespread implementation. Patients most at risk need to be identified and targeted for treatment. For disease to occur, bacterial, environmental, and nutritional factors require a genetically susceptible host. Consequently, it is important to understand how the organism interacts with the host to cause disease. Only through an understanding of what places a patient at risk can we hope to identify susceptible patients early enough in disease to have an impact on their outcome. The immune response is the single most important determinant of disease. Single nucleotide polymorphisms within the promoter region of several critical proinflammatory genes dramatically increase the risk of Helicobacter-associated gastric cancer. Additionally, environmental and dietary factors may modulate the immune response or directly influence key apoptotic and proliferative signaling cascades to alter disease presentation. Lastly, concurrent disease states may have a dramatic impact on the host response to Helicobacter infection and influence disease. An understanding of the immune signaling pathways responsible for disease and the ways in which environmental risk factors influence these pathways will allow identification of populations that are most at risk and targeted prevention and treatment strategies

Helicobacter felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice

BACKGROUND and AIMS: The impact of Helicobacter eradication therapy on the progression or regression of gastric lesions is poorly defined. This study examined the effects of eradication therapy on inflammation, atrophy, metaplasia, dysplasia, and cancer progression. METHODS: C57BL/6 mice were infected with Helicobacter felis and received bacterial eradication therapy after 2, 6, or 12 months of infection. The gastric mucosa was examined at early, mid, and late intervals after eradication and graded for histology, expression pattern of alpha-catenin and beta-catenin, and IQGAP1. RESULTS: Eradication of Helicobacter infection after 2 or 6 months of infection led to a regression of inflammation, restoration of parietal cell mass, and reestablishment of normal architecture. Progression to adenocarcinoma was prevented. Bacterial eradication at 1 year was associated with the reappearance of parietal cells, partial regression of inflammation, and restoration of architecture. Hyperplasia scores significantly improved, and dysplasia did not progress. Infected mice developed antral adenocarcinoma and gastric outlet obstruction by 24 months. Only 30% of the mice receiving bacterial eradication therapy at 12 months developed antral carcinoma. Bacterial eradication at any time during the first year of infection prevented death due to gastric outlet obstruction. The expression pattern of alpha-catenin, beta-catenin, and IQGAP1 varied with cell type and paralleled histologic changes. CONCLUSIONS: Inflammation, metaplasia, and dysplasia are reversible with early eradication therapy; progression of dysplasia was arrested with eradication therapy given as late as 1 year and prevented gastric cancer-related deaths

Gastric cancer originating from bone marrow-derived cells

Epithelial cancers are believed to originate from transformation of tissue stem cells. However, bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy. We show that although acute injury, acute inflammation, or transient parietal cell loss within the stomach do not lead to BMDC recruitment, chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, induces repopulation of the stomach with BMDCs. Subsequently, these cells progress through metaplasia and dysplasia to intraepithelial cancer. These findings suggest that epithelial cancers can originate from marrow-derived sources and thus have broad implications for the multistep model of cancer progression

ES-62 is unable to modulate Toxoplasma gondii-driven Th1 responses and pathology.

ES-62, a filarial nematode-derived anti-inflammatory immunomodulator, was administered to mice in an attempt to prevent pathology associated with Toxoplasma gondii infection. The nematode product was shown to elevate mitogen and T. gondii-specific IL-10 production but was unable to inhibit Th1 responses. Consequently ES-62 could not prevent Th1 generated immunopathology