The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

Cancer-associated fibroblasts (CAFs) are pivotal in tumor progression. TP53-deficiency in cancer cells is associated with robust stromal activation. The apelin-apelin receptor (APJ) system has been implicated in suppressing fibroblast-to-myofibroblast transition in non-neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin-APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53-wild colon cancer, HCT116, and Caco-2; TP53-mutant colon cancer, SW480, and DLD-1; and colon fibroblasts, CCD-18Co), resected human tissue samples of colorectal cancers, and immune-deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co-cultured with p53-suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ-suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast-like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma- and Mad-related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ-suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR-5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell-derived exosomes induced CAF-like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.Saiki H., Hayashi Y., Yoshii S., et al. The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells. International Journal of Oncology 63, 139 (2023); https://doi.org/10.3892/ijo.2023.5587

A novel artificial intelligence-based endoscopic ultrasonography diagnostic system for diagnosing the invasion depth of early gastric cancer

The version of record of this article, first published in Journal of Gastroenterology, is available online at Publisher’s website: https://doi.org/10.1007/s00535-024-02102-1.Background: We developed an artificial intelligence (AI)-based endoscopic ultrasonography (EUS) system for diagnosing the invasion depth of early gastric cancer (EGC), and we evaluated the performance of this system. Methods: A total of 8280 EUS images from 559 EGC cases were collected from 11 institutions. Within this dataset, 3451 images (285 cases) from one institution were used as a development dataset. The AI model consisted of segmentation and classification steps, followed by the CycleGAN method to bridge differences in EUS images captured by different equipment. AI model performance was evaluated using an internal validation dataset collected from the same institution as the development dataset (1726 images, 135 cases). External validation was conducted using images collected from the other 10 institutions (3103 images, 139 cases). Results: The area under the curve (AUC) of the AI model in the internal validation dataset was 0.870 (95% CI: 0.796–0.944). Regarding diagnostic performance, the accuracy/sensitivity/specificity values of the AI model, experts (n = 6), and nonexperts (n = 8) were 82.2/63.4/90.4%, 81.9/66.3/88.7%, and 68.3/60.9/71.5%, respectively. The AUC of the AI model in the external validation dataset was 0.815 (95% CI: 0.743–0.886). The accuracy/sensitivity/specificity values of the AI model (74.1/73.1/75.0%) and the real-time diagnoses of experts (75.5/79.1/72.2%) in the external validation dataset were comparable. Conclusions: Our AI model demonstrated a diagnostic performance equivalent to that of experts

Narrow-band imaging with magnifying endoscopy for Peyer's patches is useful in predicting the recurrence of remissive patients with ulcerative colitis

Background/AimsPeyer's patches (PPs) are aggregates of lymphoid follicles that are mainly located in the distal ileum; they play a major role in mucosal immunity. We recently reported that patients with ulcerative colitis (UC) have alterations in PPs that can be detected using narrow-band imaging with magnifying endoscopy (NBI-ME). However, the usefulness of NBI-ME in UC treatment as a whole is still unknown.MethodsWe collected NBI-ME images of PPs from 67 UC patients who had undergone ileocolonoscopy. We evaluated changes in the villi using the "villi index," which is based on three categories: irregular formation, hyperemia, and altered vascular network pattern. The patients were divided into two groups on the basis of villi index: low (L)- and high (H)-types. We then determined the correlation between morphological alteration of the PPs and various clinical characteristics. In 52 patients who were in clinical remission, we also analyzed the correlation between NBI-ME findings of PPs and clinical recurrence.ResultsThe time to clinical recurrence was significantly shorter in remissive UC patients with H-type PPs than in those with L-type PPs (P<0.01). Moreover, PP alterations were not correlated with age, sex, disease duration, clinical activity, endoscopic score, or extent of disease involvement. Multivariate analysis revealed that the existence of H-type PPs was an independent risk factor for clinical recurrence (hazard ratio, 3.3; P<0.01).ConclusionsUC patients with morphological alterations in PPs were at high risk of clinical relapse. Therefore, to predict the clinical course of UC, it may be useful to evaluate NBI-ME images of PPs

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn\u27s disease.

BACKGROUND:Small bowel stricture is one of the most common complications in patients with Crohn\u27s disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD.METHODS:Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available.RESULTS:A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation.CONCLUSIONS:In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD

Mutation of GDP-mannose-4,6-dehydratase in colorectal cancer metastasis.

Fucosylation is a crucial oligosaccharide modification in cancer. The known function of fucosylation in cancer is to mediate metastasis through selectin ligand-dependent processes. Previously, we found complete loss of fucosylation in the colon cancer cell line HCT116 due to a mutation in the GDP-fucose synthetic enzyme, GDP-mannose-4,6-dehydratase (GMDS). Loss of fucosylation led to escape of cancer cells from tumor immune surveillance followed by tumor progression and metastasis, suggesting a novel function of fucosylation in tumor progression pathway. In the present study, we investigated the frequency of GMDS mutation in a number of clinical colorectal cancer tissue samples: 81 samples of primary colorectal cancer tissue and 39 samples of metastatic lesion including liver and lymph node. Four types of deletion mutation in GMDS were identified in original cancer tissues as well as metastatic lesions. The frequency of GMDS mutation was slightly higher in metastatic lesions (12.8%, 5/39 samples) than in original cancer tissues (8.6%, 7/81 samples). No mutation of the GMDS gene was observed in normal colon tissues surrounding cancer tissues, suggesting that the mutation is somatic rather than in the germline. Immunohistochemical analysis revealed complete loss of fucosylation in three cases of cancer tissue. All three cases had GMDS mutation. In one of three cases, loss of fucosylation was observed in only metastatic lesion, but not its original colon cancer tissue. These data demonstrate involvement of GMDS mutation in the progression of colorectal cancer

Efficacy of Serotonin Type 3 Receptor Antagonist Ramosetron on Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D)-Like Symptoms in Patients with Quiescent Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

Patients with quiescent inflammatory bowel disease (IBD) frequently suffer diarrhea-predominant irritable bowel syndrome (IBS-D)-like symptoms, such as abdominal pain or stool irregularities. Here, we assessed the effect of ramosetron, a serotonin type 3 (5-HT3) receptor antagonist, on IBS-D-like symptoms in patients with quiescent IBD. Seventy patients with quiescent IBD, who met the Rome III diagnostic criteria for IBS-D, were randomly assigned to receive either ramosetron (5 μg; n = 35) or a placebo (n = 35) orally once daily for 4 weeks. The primary endpoint was the responder rate for global assessment of relief from overall IBS-D-like symptoms. The responder rates for relief of abdominal pain/discomfort and improvement of bowel habits were also evaluated. The responder rate for relief from overall IBS-D-like symptoms at the final evaluation point was significantly higher in the ramosetron group (35.5%) than in the placebo group (11.4%) (p = 0.037). The responder rate for improvement of bowel habits was significantly higher in the ramosetron group (38.7%) than in the placebo group (14.3%) (p = 0.028). The reduction of stool frequency was significantly greater in the ramosetron group than in the placebo group (p = 0.044). Ramosetron is effective for relief of overall IBS-D-like symptoms in patients with quiescent IBD

Fucosylation Is a Promising Target for Cancer Diagnosis and Therapy

Oligosaccharides, sequences of carbohydrates conjugated to proteins and lipids, are arguably the most abundant and structurally diverse class of molecules. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. Recent advances in glycomics have identified several types of glyco-biomarkers containing fucosylation that are linked to certain types of cancer. Fucosylated alpha-fetoprotein (AFP) is widely used in the diagnosis of hepatocellular carcinoma because it is more specific than alpha-fetoprotein. High levels of fucosylated haptoglobin have also been found in sera of patients with various carcinomas. We have recently established a simple lectin-antibody ELISA to measure fucosylated haptoglobin and to investigate its clinical use. Cellular fucosylation is dependent upon fucosyltransferase activity and the level of its donor substrate, guanosine diphosphate (GDP)-fucose. GDP-mannose-4,6-dehydratase (GMDS) is a key enzyme involved in the synthesis of GDP-fucose. Mutations of GMDS found in colon cancer cells induced a malignant phenotype, leading to rapid growth in athymic mice resistant to natural killer cells. This review describes the role of fucosylated haptoglobin as a cancer biomarker, and discusses the possible biological role of fucosylation in cancer development