Gastrin and upper GI cancers

Hayakawa, Yoku; Chang, Wenju; Jin, Guangchun; Wang, Yichen

doi:10.1016/j.coph.2016.08.013

Cited by 54 publications

(51 citation statements)

References 59 publications

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“…Through lineage tracing experiments, Hayakawa et al73, 74 reported that the CCK-B receptor expression in the stomach antrum is expressed in position 4+ of antral stem cells and responds to progastrin rather than gastrin-17. In the gastric cardia CCK-B receptors are found on position 4+ stem cells, but unlike the antral stem cells these cells respond to the proliferative actions of amidated gastrin-17 74, 75. In the body of the stomach, the CCK-B receptors on the parietal cells, ECL cells, and cells in the isthmus also respond to gastrin-17 48, 75, 76…”

Section: Expression Of Gastrin and The Cck-b Receptors In Gastric Canmentioning

confidence: 99%

“…In the gastric cardia CCK-B receptors are found on position 4+ stem cells, but unlike the antral stem cells these cells respond to the proliferative actions of amidated gastrin-17 74, 75. In the body of the stomach, the CCK-B receptors on the parietal cells, ECL cells, and cells in the isthmus also respond to gastrin-17 48, 75, 76…”

Section: Expression Of Gastrin and The Cck-b Receptors In Gastric Canmentioning

confidence: 99%

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Gastrin and Gastric Cancer

Smith

Nadella

Osborne

2017

Cellular and Molecular Gastroenterology and Hepatology

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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. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin’s actions are mediated through the G-protein–coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor–induced hypergastrinemia and infection with Helicobacter pylori increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune-based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer.

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Section: Expression Of Gastrin and The Cck-b Receptors In Gastric Canmentioning

confidence: 99%

Section: Expression Of Gastrin and The Cck-b Receptors In Gastric Canmentioning

confidence: 99%

Gastrin and Gastric Cancer

Smith

Nadella

Osborne

2017

Cellular and Molecular Gastroenterology and Hepatology

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“…Importantly, the expression of CCK2R in antral +4 stem cells potentially explains the gastrin-mediated effects on cancer progression in mouse models 62 . In mice, increased levels of amidated gastrin promote proximal corpus carcinogenesis but inhibit antral cancer development, whereas knockout of gastrin promotes antral cancer development 41, 63, 64, 65.…”

mentioning

confidence: 99%

“…In the antrum, amidated gastrin suppresses CCK2R + stem cell activity 57 ; on the other hand, CCK2R-expressing stem cells in the cardia and progenitors in the corpus are activated by amidated gastrin 45 (Figure 2). Therefore, CCK2R modulates proximal and distal gastric stem cells in distinct ways, and thus cancer risk 62 . In recent decades, there has been a dramatic epidemiologic shift in the location of gastric cancer, with a decrease in antral cancer and an increase in proximal corpus/cardia cancer 38 .…”

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confidence: 99%

The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models

Hayakawa

Fox

Wang

2017

Cellular and Molecular Gastroenterology and Hepatology

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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. The gastric corpus and antrum have distinct stem cells and stem cell niches, suggesting differential regulation of cancer initiation at the 2 sites. In this short review, we discuss recent experimental models and human studies, which provide important insights into the pathogenesis of gastric cancer.

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“…Human Barrett’s esophagus and gastric cardia exhibit strong expression of CCK2R (a gastrin receptor), and progression of Barrett’s-like metaplasia in mice is accelerated by hypergastrinemia and inhibited by CCK2R blockade. 62,63 Gamma-secretase inhibitors, which block Notch signaling, increase goblet cells and reduce proliferation in rodent Barrett’s metaplasia, suggesting that Notch signaling might drive neoplastic progression. 61,62 Dr Wang concluded that the abundance and activity of undifferentiated stem cells, rather than the presence of goblet cells, likely drives cancer risk in Barrett’s esophagus.…”

Section: Potential Origins Of Metaplasia In the Esophagus And Stomachmentioning

confidence: 99%