Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find ...that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.
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•NGF expression is induced in gastric cancer by ACh from nerves and tuft cells•NGF promotes innervation and proliferation in gastric epithelium•Blockade of NGF or ablation of cholinergic tuft cells inhibits tumor development•Cholinergic signaling activates YAP signaling that is essential for Wnt activation
Hayakawa et al. use a series of mouse models to show that acetylcholine from Dclk1+ tuft cells and nerves induces NGF in gastric epithelial cells, which promotes neuron expansion and tumorigenesis. YAP is activated through the cholinergic signaling, and inhibition of this pathway can block NGF-driven tumors.
To investigate the clinicopathological features of the patients testing negative for high titer serum anti-
(
) antibody.
The antibody titers were measured using antigens derived from Japanese ...individuals.
C-urea breath test-positive individuals were defined as having
infection. We investigated the demographic characteristics, laboratory data, endoscopic findings including Kyoto classification of gastritis, and histology in negative-high titer patients without
eradication therapy. Kyoto classification consisted of scores for gastric atrophy, intestinal metaplasia, enlarged folds, nodularity, and redness.
Of the 136 subjects enrolled, 23 (17%) had
infection. Kyoto classification had an excellent area under the receiver operating characteristics curve (0.886, 95% confidence interval: 0.803-0.968,
= 3.7 × 10
) for predicting
infection with a cut-off value of 2. Further, Kyoto classification,
density, and neutrophil activity had high accuracies (89.7%, 96.3%, and 94.1%, respectively). Kyoto classification was independent of the demographic and laboratory parameters in multivariate analysis.
Endoscopic Kyoto classification of gastritis is a useful predictor of
infection in negative-high titer antibody patients.
Background
Two methods are used to evaluate gastritis: the updated Sydney system (USS) with pathology and Kyoto classification, a new endoscopy‐based diagnostic criterion for which evidence is ...accumulating. However, the consistency of their results is unclear. This study investigated the consistency of their results.
Methods
Patients who underwent esophagogastroduodenoscopy and were evaluated for Helicobacter pylori infection for the first time were eligible. The association between corpus and antral USS scores (neutrophil activity, chronic inflammation, atrophy, and intestinal metaplasia) and Kyoto classification scores (atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness) was assessed.
Results
Seven‐hundred‐seventeen patients (mean age, 49.2 years; female sex, 57.9%; 450 H. pylori‐positive and 267 H. pylori‐negative patients) were enrolled. All endoscopic gastritis cases in the Kyoto classification were associated with high corpus and antral USS scores for neutrophil activity and chronic inflammation. A subanalysis was performed for H. pylori‐positive patients. Regarding atrophy and intestinal metaplasia, endoscopic findings were associated with USS scores. Enlarged folds, nodularity, and diffuse redness were associated with high corpus USS scores for neutrophil activity and chronic inflammation, but with low antral USS scores for atrophy and intestinal metaplasia. The Kyoto classification scores were also associated with the pathological topographic distribution of neutrophil activity and intestinal metaplasia.
Conclusions
Among H. pylori‐positive individuals, endoscopic and pathological diagnoses were consistent with atrophy and intestinal metaplasia. Enlarged folds, nodularity, and diffuse redness were associated with pathological inflammation (neutrophil activity and chronic inflammation) of the corpus; however, they were inversely associated with pathological atrophy and intestinal metaplasia. The endoscopy‐based Kyoto classification of gastritis partially reflects pathology.
E-cadherin is an important adhesion molecule whose loss is associated with progression and poor prognosis of liver cancer. However, it is unclear whether the loss of E-cadherin is a real culprit or a ...bystander in liver cancer progression. In addition, the precise role of E-cadherin in maintaining liver homeostasis is also still unknown, especially in vivo. Here we demonstrate that liver-specific E-cadherin knockout mice develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction. Furthermore, a few of the E-cadherin knockout mice developed spontaneous liver cancer. When knockout of E-cadherin is combined with Ras activation or chemical carcinogen administration, E-cadherin knockout mice display markedly accelerated carcinogenesis and an invasive phenotype associated with epithelial–mesenchymal transition, up-regulation of stem cell markers, and elevated ERK activation. Also in human hepatocellular carcinoma, E-cadherin loss correlates with increased expression of mesenchymal and stem cell markers, and silencing of E-cadherin in hepatocellular carcinoma cell lines causes epithelial–mesenchymal transition and increased invasiveness, suggesting that E-cadherin loss can be a causal factor of these phenotypes. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.
The prevalence of Helicobacter pylori (H. pylori) has decreased during several decades due to improvements in the sanitary environment in Japan. Consequently, a relative increase in the incidence of ...H. pylori-uninfected gastric cancer is expected. We analyzed the trends in H. pylori-uninfected gastric cancer. Two hundred fifty-eight patients with gastric cancer were retrospectively analyzed. The study was divided into four periods: 2008–2011 (first period), 2012–2014 (second period), 2015–2017 (third period), and 2018–2021 (fourth period). The status of H. pylori infection was divided into four categories: uninfected, successful eradication, spontaneous eradication, and persistent infection. Gastric mucosal atrophy was divided into six grades according to the Kimura–Takemoto classification. The proportion of H. pylori infections significantly changed over the study period (p = 0.007). In particular, the rate of H. pylori-uninfected gastric cancer tended to increase over time (0%, 2.9%, 4.9%, and 13.4% in the first, second, third, and fourth periods, respectively; p = 0.0013). The rate of no atrophy (C-0) in gastric cancer tended to increase over time (0%, 2.9%, 4.9%, and 11.0% in the first, second, third, and fourth periods, respectively; p = 0.0046). In conclusion, the rate of H. pylori-uninfected gastric cancer without gastric atrophy tended to increase over time.
We have previously reported that
(
)-associated nodular gastritis could occur in both the antrum and the cardia. Cardiac nodularity-like appearance (hereafter, called as cardiac nodularity) had a ...high predictive accuracy for the diagnosis of
infection. In the previous study, we included only the patients who were evaluated for
infection for the first time, and excluded patients with a history of eradication. Therefore, the prevalence and clinical features of cardiac nodularity remains unknown.
To perform this cross-sectional study to explore the characteristics of cardiac nodularity.
Consecutive patients who underwent esophagogastroduodenoscopy between May, 2017 and August, 2019 in the Toyoshima Endoscopy Clinic were enrolled in this study. We included
-negative,
-positive, and
-eradicated patients, and excluded patients with unclear
status and eradication failure.
infection was diagnosed according to serum anti-
antibody and the urea breath test or histology. Cardiac nodularity was defined as a miliary nodular appearance or the presence of scattered whitish circular small colorations within 2 cm of the esophagogastric junction. Nodularity was visualized as whitish in the narrow-band imaging mode. We collected data on the patients' baseline characteristics.
A total of 1078 patients were finally included. Among
-negative patients, cardiac nodularity and antral nodularity were recognized in 0.14% each. Among
-positive patients, cardiac nodularity and antral nodularity were recognized in 54.5% and 29.5%, respectively. Among
-eradicated patients, cardiac nodularity and antral nodularity were recognized in 4.5% and 0.6%, respectively. The frequency of cardiac nodularity was significantly higher than that of antral nodularity in
-positive and -eradicated patients. The frequencies of cardiac nodularity and antral nodularity in
-eradicated patients were significantly lower than those in
-positive patients (
< 0.001). The patients with cardiac nodularity were significantly younger than those without cardiac nodularity (
= 0.0013). Intestinal metaplasia score of the patients with cardiac nodularity were significantly lower than those without cardiac nodularity (
= 0.0216). Among
-eradicated patients, the patients with cardiac nodularity underwent eradication significantly more recently compared with those without cardiac nodularity (
< 0.0001).
This report outlines the prevalence and clinical features of cardiac nodularity, and confirm its close association with active
infection.
Aside from the human epidermal growth factor receptor‐2 (HER2)‐targeting agent trastuzumab, molecular targeting therapy for gastric cancer (GC) has not been established. We previously reported that ...apoptosis signal‐regulating kinase‐1 (ASK1) was upregulated in human GC and that overexpression of ASK1 promoted GC cell proliferation. Here, we investigated the effect of ASK1 inhibitor K811 on GC cells. K811 efficiently prevented cell proliferation in cell lines with high ASK1 expression and in HER2‐overexpressing GC cells. Treatment with K811 reduced sizes of xenograft tumors by downregulating proliferation markers. These results indicate that ASK1 inhibition prevents GC cell growth in vitro and in vivo, suggesting that ASK1 inhibitors can be potent therapeutic drugs for GC.
Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and ...clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/-)) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/-) mice, compared with WT mice. Impaired tumor development in IL-6(-/-) mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine if a discrepancy exists between subjective symptoms and the grade of endoscopic gastroesophageal reflux disease (GERD) in diabetes mellitus (DM) patients.
All 2,884 patients who ...underwent esophagogastroduodenoscopy completed the modified Gastrointestinal Symptom Rating Scale (GSRS), an interview-based rating scale consisting of 16 items including a question on acid regurgitation. Patients were divided into DM and non-DM groups (1,135 and 1,749 patients, respectively). GERD was diagnosed endoscopically and graded according to the Los Angeles classification. Grade B or more severe GERD was defined as severe endoscopic GERD. The intergroup GSRS score was compared statistically.
In severe endoscopic GERD patients, the prevalence of patients with a positive GSRS score in the acid regurgitation question was statistically lower in DM patients than non-DM patients. Of the 60 non-DM patients with severe endoscopic GERD, 40 patients (67%) had a positive GSRS score for acid regurgitation; however, of the 51 DM patients with severe endoscopic GERD, 23 patients (45%) had a positive GSRS score. Multivariate analysis showed that severe endoscopic GERD (OR: 2.01; 95% CI: 1.21-3.33; p = 0.0066), non-DM (OR: 0.74; 95% CI: 0.54-0.94; p = 0.0157), younger age (OR: 0.98; 95% CI: 0.97-0.99; p = 0.0125), and hiatal hernia (OR: 1.46; 95% CI: 1.12-1.90; p = 0.0042) were associated with acid regurgitation symptoms.
There is a discrepancy between subjective symptoms and endoscopic GERD grade in DM patients. The ability of DM patients to feel acid regurgitation may be decreased.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Helicobacter pylori eradication therapy is commonly performed to reduce the incidence of gastric cancer. However, gastric cancer is occasionally discovered even after successful ...eradication therapy. Therefore, we examined the prognosis of gastric cancer patients, diagnosed after successful H. pylori eradication therapy.
Materials and Methods
All‐cause death rates and gastric cancer‐specific death rates in gastric cancer patients who received successful H. pylori eradication treatment was tracked and compared to rates in patients who did not receive successful eradication therapy.
Results
In total, 160 gastric cancer patients were followed‐up for up to 11.7 years (mean 3.5 years). Among them, 53 gastric cancer patients received successful H. pylori eradication therapy prior to gastric cancer diagnosis. During the follow‐up period, 11 all‐cause deaths occurred. In the successful eradication group, the proportion of patients with cancer stage I was higher. The proportions of patients who received curative endoscopic therapy and endoscopic examination in the 2 years prior to gastric cancer diagnosis were also higher in the successful eradication group. Kaplan–Meier analysis of all‐cause death and gastric cancer‐specific death revealed a lower death rate in patients in the successful eradication group (P = .0139, and P = .0396, respectively, log‐rank test). The multivariate analysis showed that endoscopy within 2 years before cancer diagnosis is associated with stage I cancer.
Conclusions
Possible early discovery of gastric cancer after H. pylori eradication due to regular endoscopic surveillance may contribute to better prognosis of patients with gastric cancer.
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