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2017: AGA-R. Robert and Sally Funderburg Research Award in Gastric Cancer 25th Anniversary Tribute
Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells
Gastric cancer is the third most common cause of cancer-related death. Although the incidence of gastric cancer in the United States is relatively low, it remains significantly higher in some countries, including Japan and Korea. Interactions between cancer stem cells and the tumor microenvironment can have a substantial impact on tumor characteristics and contribute to heterogeneity. The mechanisms responsible for maintaining malignant cancer stem cells within the tumor microenvironment in human gastric cancer are largely unknown.Gastrin and Gastric Cancer
Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer.Regulation of Gastric Carcinogenesis by Inflammatory Cytokines
Chronic inflammation caused by infection with Helicobacter pylori and autoimmune gastritis increases an individual’s risk of developing gastric cancer. More than 90% of gastric cancers are adenocarcinomas, which originate from epithelial cells in the chronically inflamed gastric mucosa. However, only a small subset of chronic gastritis patients develops gastric cancer, implying a role for genetic and environmental factors in cancer development. A number of DNA polymorphisms that increase gastric cancer risk have mapped to genes encoding cytokines.Honoring the 25th Anniversary of the AGA–R. Robert and Sally Funderburg Research Award in Gastric Cancer
In 2017, Cellular and Molecular Gastroenterology and Hepatology is pleased to honor the 25th anniversary of the AGA–R. Robert and Sally Funderburg Research Award in Gastric Cancer with a compendium of reviews and commentaries written by recipients of this award. The AGA–R. Robert and Sally Funderburg Research Award in Gastric Cancer recognizes and supports an established investigator whose research will enhance the fundamental understanding of gastric cancer pathobiology to ultimately prevent, or develop a cure for, the disease.Historical Perspective on Familial Gastric Cancer
Gastric cancer is a common disease worldwide, typically associated with acquired chronic inflammation in the stomach, related in most instances to infection by Helicobacter pylori. A small percentage of cases occurs in familial clusters, and some of these can be linked to specific germline mutations. This article reviews the historical background to the current understanding of familial gastric cancer, focuses on the entity of hereditary diffuse gastric cancer, and also reviews the risks for gastric cancer related to a number of other familial genetic diseases.The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models
The cellular origin of digestive cancers has been a long-standing question in the cancer field. Mouse models have identified long-lived stem cells in most organ systems, including the luminal gastrointestinal tract, and numerous studies have pointed to tissue resident stem cells as the main cellular origin of cancer. During gastric carcinogenesis, chronic inflammation induces genetic and epigenetic alterations in long-lived stem cells, along with expansion of stem cell niches, eventually leading to invasive cancer.Regulation of Gastric Metaplasia, Dysplasia, and Neoplasia by Bone Morphogenetic Protein Signaling
The bone morphogenetic proteins, (BMP)s are regulatory peptides that have significant effects on the growth and differentiation of gastrointestinal tissues. In addition, the BMPs have been shown to exert anti-inflammatory actions in the gut and to negatively regulate the growth of gastric neoplasms. The role of BMP signaling in the regulation of gastric metaplasia, dysplasia and neoplasia has been poorly characterized. Transgenic expression in the mouse stomach of the BMP inhibitor noggin leads to decreased parietal cell number, increased epithelial cell proliferation, and to the emergence of SPEM.Oxidative Stress Resulting From Helicobacter pylori Infection Contributes to Gastric Carcinogenesis
Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the host’s efforts to kill the bacteria.Gastric Cancer in the Era of Precision Medicine
Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients.Genomics, Endoscopy, and Control of Gastroesophageal Cancers: A Perspective
In The Cancer Genome Atlas the goals were to define how to treat advanced cancers with targeted therapy. However, the challenges facing cancer interception for early detection and prevention include length bias in which current screening and surveillance approaches frequently miss rapidly progressing cancers that then present at advanced stages in the clinic with symptoms (underdiagnosis). In contrast, many early detection strategies detect benign conditions that may never progress to cancer during a lifetime, and the patient dies of unrelated causes (overdiagnosis).Notch as a Driver of Gastric Epithelial Cell Proliferation
The gastric epithelium is sustained by a population of stem cells that replenish the various mature epithelial lineages throughout adulthood. Regulation of stem and progenitor cell proliferation occurs via basic developmental signaling pathways, including the Notch pathway, which recently was described to promote gastric stem cell proliferation in both mice and human beings. Current cancer theory proposes that adult stem cells that maintain gastrointestinal tissues accumulate mutations that promote cancerous growth, and that basic signaling pathways, such as Notch, which stimulate stem cell proliferation, can promote tumorigenesis.Gastric Cancer Genomics: Advances and Future Directions
Advancement in the field of cancer genomics is revolutionizing the molecular characterization of a wide variety of different cancers. Recent application of large-scale, next-generation sequencing technology to gastric cancer, which remains a major source of morbidity and mortality throughout the world, has helped better define the complex genomic landscape of this cancer. These studies also have led to the development of novel genomically based molecular classification systems for gastric cancer, reinforced the importance of classic driver mutations in gastric cancer pathogenesis, and led to the discovery of new driver gene mutations that previously were not known to be associated with gastric cancer.Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions
Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation.The Clinical Evidence Linking Helicobacter pylori to Gastric Cancer
Gastric cancer has long been recognized to be accompanied and preceded by chronic gastritis, lasting decades. Arguably, the most important development in our understanding of gastric cancer pathogenesis over the past 50 years has been the realization that, for most cases of gastric cancer, Helicobacter pylori is the cause of the underlying gastritis. Gastritis can promote gastric carcinogenesis, typically via the Correa cascade of atrophic gastritis, intestinal metaplasia, and dysplasia. Nested case-control studies have shown that H pylori infection increases the risk of gastric cancer significantly, both of the intestinal and diffuse subtypes, and that H pylori is responsible for approximately 90% of the world’s burden of noncardia gastric cancer.Murine Models of Gastric Corpus Preneoplasia
Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers.
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