Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 102
Filtrar
1.
Endoscopy ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607377

RESUMO

INTRODUCTION AND AIMS: To compare endoscopy gastric cancer images diagnosis rate between artificial intelligence (AI) and expert endoscopists. PATIENTS AND METHODS: We used the retrospective data of 500 patients, including 100 with gastric cancer, matched 1:1 to diagnosis by AI or expert endoscopists. We retrospectively evaluated the non-inferiority (prespecified margin 5%) of the per-patient rate of gastric cancer diagnosis by AI and compared the per-image rate of gastric cancer diagnosis. RESULTS: Gastric cancer was diagnosed in 49 of 49 patients (100%) in the AI group and 48 of 51 patients (94.12%) in the expert endoscopist group (difference 5.88, 95% confidence interval: -0.58 to 12.3). The per-image rate of gastric cancer diagnosis was higher in the AI group (99.87%, 747/748 images) than in the expert endoscopist group (88.17%, 693/786 images) (difference 11.7%). CONCLUSIONS: Non inferiority of the rate of gastric cancer diagnosis by AI was demonstrated but superiority is not demonstrated.

2.
Science ; 373(6561): eabj0486, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34529467
3.
JHEP Rep ; 3(4): 100315, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34345813

RESUMO

Background & Aims: Liver lobules are typically subdivided into 3 metabolic zones: zones 1, 2, and 3. However, the contribution of zonal differences in hepatocytes to liver regeneration, as well as to carcinogenic susceptibility, remains unclear. Methods: We developed a new method for sustained genetic labelling of zone 3 hepatocytes and performed fate tracing to monitor these cells in multiple mouse liver tumour models. Results: We first examined changes in the zonal distribution of the Wnt target gene Axin2 over time using Axin2-Cre ERT2 ;Rosa26-Lox-Stop-Lox-tdTomato mice (Axin2;tdTomato). We found that following tamoxifen administration at 3 weeks of age, approximately one-third of total hepatocytes that correspond to zone 3 were labelled in Axin2;tdTomato mice; the tdTomato+ cell distribution closely matched that of the zone 3 marker CYP2E1. Cell fate analysis revealed that zone 3 hepatocytes maintained their own lineage but rarely proliferated beyond their liver zonation during homoeostasis; this indicated that our protocol enabled persistent genetic labelling of zone 3 hepatocytes. Using this system, we found that zone 3 hepatocytes generally had high neoplastic potential, which was promoted by constitutive activation of Wnt/ß-catenin signalling in the pericentral area. However, the frequency of zone 3 hepatocyte-derived tumours varied depending on the regeneration pattern of the liver parenchyma in response to liver injury. Notably, Axin2-expressing hepatocytes undergoing chronic liver injury significantly contributed to liver regeneration and possessed high neoplastic potential. Additionally, we revealed that the metabolic phenotypes of liver tumours were acquired during tumorigenesis, irrespective of their spatial origin. Conclusions: Hepatocytes receiving Wnt/ß-catenin signalling from their microenvironment have high neoplastic potential, and Wnt/ß-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma. Lay summary: Lineage tracing revealed that zone 3 hepatocytes residing in the pericentral niche have high neoplastic potential. Under chronic liver injury, hepatocytes receiving Wnt/ß-catenin signalling broadly exist across all hepatic zones and significantly contribute to liver tumorigenesis as well as liver regeneration. Wnt/ß-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma.

5.
JGH Open ; 5(7): 770-777, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34263071

RESUMO

Background and Aim: Proton pump inhibitors (PPIs) are a potential cause of gastric carcinogenesis after Helicobacter pylori eradication. Thus, appropriate management including chemoprevention is required. The aim of this study was to evaluate the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and the incidence of post-eradication gastric cancer in PPI users. Methods: A multicenter retrospective cohort study was conducted. Patients who used a PPI (≥30 days) after H. pylori eradication between 2014 and 2019 were analyzed in nine hospital databases. Gastric cancer incidence was a primary outcome, and their association with NSAIDs use and clinical factors was evaluated. Hazard ratios were adjusted by age, sex, smoking, and Charlson Comorbidity Index. Results: During the mean follow-up period of 2.38 years, 1.13% (31/2431) of all patients developed gastric cancer. The cumulative incidence of gastric cancer in PPI users was 0.25% at 1 year, 0.51% at 3 years, and 1.09% at 5 years in the NSAID users and 0.89% at 1 year, 2.32% at 3 years, and 3.61% at 5 years in nonusers. NSAIDs were associated with a lower gastric cancer risk (adjusted hazard ratio = 0.28, P = 0.005). No gastric cancer was observed in the cyclooxygenase-2 inhibitor users (n = 256). NSAID use with high dose and long duration was significantly associated with a lower incidence of gastric cancer. Conclusion: NSAIDs were associated with a 60% decrease in the gastric cancer incidence in H. pylori-eradicated PPI users, with dose and duration response effects. NSAIDs may be effective for chemoprevention against PPI-related gastric cancer.

7.
Cell Stem Cell ; 28(8): 1343-1361, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34129814

RESUMO

The esophagus and stomach, joined by a unique transitional zone, contain actively dividing epithelial stem cells required for organ homeostasis. Upon prolonged inflammation, epithelial cells in both organs can undergo a cell fate switch leading to intestinal metaplasia, predisposing to malignancy. Here we discuss the biology of gastroesophageal stem cells and their role as cells of origin in cancer. We summarize the interactions between the stromal niche and gastroesophageal stem cells in metaplasia and early expansion of mutated stem-cell-derived clones during carcinogenesis. Finally, we review new approaches under development to better study gastroesophageal stem cells and advance the field.


Assuntos
Esôfago de Barrett , Neoplasias , Humanos , Metaplasia , Células-Tronco
8.
Biology (Basel) ; 10(6)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067300

RESUMO

Metachronous gastric cancer often occurs after endoscopic resection. Appropriate management, including chemoprevention, is required after the procedure. This study was performed to evaluate the association between medication use and the incidence of metachronous gastric cancer after endoscopic resection. This multicenter retrospective cohort study was conducted with data from nine hospital databases on patients who underwent endoscopic resection for gastric cancer between 2014 and 2019. The primary outcome was the incidence of metachronous gastric cancer. We evaluated the associations of metachronous gastric cancer occurrence with medication use and clinical factors. Hazard ratios were adjusted by age and Charlson comorbidity index scores, with and without consideration of sex, smoking status, and receipt of Helicobacter pylori eradication therapy during the study period. During a mean follow-up period of 2.55 years, 10.39% (140/1347) of all patients developed metachronous gastric cancer. The use of antibiotics other than those used for H. pylori eradication was associated with a lower incidence of metachronous gastric cancer than was non-use (adjusted hazard ratio (aHR) 0.56, 95% confidence interval (CI) 0.38-0.85, p = 0.006). Probiotic drug use was also associated with a lower incidence of metachronous gastric cancer compared with non-use (aHR 0.29, 95% CI 0.091-0.91, p = 0.034). In conclusion, the use of antibiotics and probiotic drugs was associated with a decreased risk of metachronous gastric cancer. These findings suggest that the gut microbiome is associated with metachronous gastric cancer development.

9.
Cell Host Microbe ; 29(6): 941-958.e10, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-33989515

RESUMO

Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis.


Assuntos
Antígenos de Bactérias/metabolismo , Proteína BRCA1/metabolismo , Proteínas de Bactérias/metabolismo , Células Epiteliais/metabolismo , Instabilidade Genômica , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Neoplasias Gástricas/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinogênese/metabolismo , Linhagem Celular , Quebras de DNA de Cadeia Dupla , Células Epiteliais/microbiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Estômago/microbiologia , Proteína Supressora de Tumor p53/metabolismo
10.
Sci Rep ; 11(1): 7200, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785826

RESUMO

The intestinal stroma provides an important microenvironment for immune cell activation. The perturbation of this tightly regulated process can lead to excessive inflammation. We know that upregulated Toll-like receptor 4 (TLR4) in the intestinal epithelium plays a key role in the inflammatory condition of preterm infants, such as necrotizing enterocolitis (NEC). However, the surrounding stromal contribution to excessive inflammation in the pre-term setting awaits careful dissection. Ex vivo co-culture of embryonic day 14.5 (E14.5) or adult murine intestinal stromal cells with exogenous monocytes was undertaken. We also performed mRNAseq analysis of embryonic and adult stromal cells treated with vehicle control or lipopolysaccharide (LPS), followed by pathway and network analyses of differentially regulated transcripts. Cell characteristics were compared using flow cytometry and pHrodo red phagocytic stain, candidate gene analysis was performed via siRNA knockdown and gene expression measured by qPCR and ELISA. Embryonic stromal cells promote the differentiation of co-cultured monocytes to CD11bhighCD11chigh mononuclear phagocytes, that in turn express decreased levels of CD103. Global mRNAseq analysis of stromal cells following LPS stimulation identified TLR signaling components as the most differentially expressed transcripts in the immature compared to adult setting. We show that CD14 expressed by CD11b+CD45+ embryonic stromal cells is a key inducer of TLR mediated inflammatory cytokine production and phagocytic activity of monocyte derived cells. We utilise transcriptomic analyses and functional ex vivo modelling to improve our understanding of unique molecular cues provided by the immature intestinal stroma.


Assuntos
Enterocolite Necrosante/patologia , Inflamação/patologia , Intestinos/patologia , Monócitos/patologia , Células Estromais/patologia , Animais , Células Cultivadas , Técnicas de Cocultura , Enterocolite Necrosante/genética , Redes Reguladoras de Genes , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Inflamação/genética , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Células Estromais/metabolismo , Transcriptoma
11.
Digestion ; 102(6): 845-853, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33592610

RESUMO

INTRODUCTION AND AIMS: This international survey was performed to evaluate the cumulative incidence of nosocomial novel coronavirus disease 2019 (COVID-19) among healthcare professionals during endoscopic procedures. METHODS: We performed an international web-based self-reported questionnaire survey. Participants completed the questionnaires every week for 12 weeks. The questionnaire elicited responses regarding the development of COVID-19 and details of the personal protective equipment (PPE) used. RESULTS: All 483 participants were included in the analysis. Participants had a mean age of 42.3 years and comprised 68.3% males. The geographic distribution of the study population was Asia (89.2%), Europe (2.9%), North and South America (4.8%), Oceania (0.6%), and Africa (1.5%). The most common endoscopy-related role of the participants was endoscopist (78.7%), and 74.5% had >10 years of experience. Fourteen participants had performed 83 endoscopic procedures in patients positive for COVID-19. During the mean follow-up period of 4.95 weeks, there were no cases of COVID-19 when treating COVID-19 positive patients. The most common PPE used by participants treating patients with COVID-19 was a surgical mask plus N95 mask plus face shield, goggles, cap, long-sleeved isolation gown, and single pair of gloves. The most common PPE used by participants treating patients without COVID-19 was a surgical mask, no face shield but goggles, cap, long-sleeved isolation gown, and single pair of gloves during all endoscopic procedures. CONCLUSIONS: The risk of COVID-19 transmission during any endoscopic procedure was low in clinical practice.


Assuntos
COVID-19 , Equipamento de Proteção Individual , Adulto , Endoscopia , Feminino , Humanos , Transmissão de Doença Infecciosa do Paciente para o Profissional , Masculino , SARS-CoV-2 , Inquéritos e Questionários
12.
Gastroenterology ; 160(6): 2133-2148.e6, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33465373

RESUMO

BACKGROUND & AIMS: Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. METHODS: We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-CreERT mice. RESULTS: Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs showed gradual replacement by CK19- cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2+ PBG cells, but not CK19+ luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor. CONCLUSION: A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma.


Assuntos
Ampola Hepatopancreática , Proteína Axina/metabolismo , Carcinoma/patologia , Neoplasias do Ducto Colédoco/patologia , Células Epiteliais/patologia , Células-Tronco/patologia , Via de Sinalização Wnt , Ampola Hepatopancreática/patologia , Animais , Proteína Axina/genética , Ductos Biliares Extra-Hepáticos/metabolismo , Ductos Biliares Extra-Hepáticos/patologia , Carcinogênese/genética , Linhagem da Célula , Proliferação de Células , Células Epiteliais/metabolismo , Queratina-19/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , PTEN Fosfo-Hidrolase/genética , Esfíncter da Ampola Hepatopancreática/metabolismo , Células-Tronco/metabolismo , Trombospondinas/genética , Trombospondinas/metabolismo
13.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G506-G520, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33470182

RESUMO

The stem/progenitor cells of the developing intestine are biologically distinct from their adult counterparts. Here, we examine the microenvironmental cues that regulate the embryonic stem/progenitor population, focusing on the role of Notch pathway factor delta-like protein-1 (DLK1). mRNA-seq analyses of intestinal mesenchymal cells (IMCs) collected from embryonic day 14.5 (E14.5) or adult IMCs and a novel coculture system with E14.5 intestinal epithelial organoids were used. Following addition of recombinant DLK1 (rDLK) or Dlk1 siRNA (siDlk1), epithelial characteristics were compared using imaging, replating efficiency assays, qPCR, and immunocytochemistry. The intestinal phenotypes of littermate Dlk1+/+ and Dlk1-/- mice were compared using immunohistochemistry. Using transcriptomic analyses, we identified morphogens derived from the embryonic mesenchyme that potentially regulate the developing epithelial cells, to focus on Notch family candidate DLK1. Immunohistochemistry indicated that DLK1 was expressed exclusively in the intestinal stroma at E14.5 at the top of emerging villi, decreased after birth, and shifted to the intestinal epithelium in adulthood. In coculture experiments, addition of rDLK1 to adult IMCs inhibited organoid differentiation, whereas Dlk1 knockdown in embryonic IMCs increased epithelial differentiation to secretory lineage cells. Dlk1-/- mice had restricted Ki67+ cells in the villi base and increased secretory lineage cells compared with Dlk1+/+ embryos. Mesenchyme-derived DLK1 plays an important role in the promotion of epithelial stem/precursor expansion and prevention of differentiation to secretory lineages in the developing intestine.NEW & NOTEWORTHY Using a novel coculture system, transcriptomics, and transgenic mice, we investigated differential molecular signaling between the intestinal epithelium and mesenchyme during development and in the adult. We show that the Notch pathway factor delta-like protein-1 (DLK1) is stromally produced during development and uncover a new role for DLK1 in the regulation of intestinal epithelial stem/precursor expansion and differentiation to secretory lineages.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Comunicação Celular , Diferenciação Celular , Proliferação de Células , Células-Tronco Embrionárias/enzimologia , Células Epiteliais/enzimologia , Mucosa Intestinal/enzimologia , Células Estromais/enzimologia , Animais , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Linhagem da Célula , Células Cultivadas , Técnicas de Cocultura , Regulação da Expressão Gênica no Desenvolvimento , Mucosa Intestinal/embriologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organoides , Via Secretória , Transdução de Sinais , Nicho de Células-Tronco , Transcriptoma
14.
Gastroenterology ; 160(3): 781-796, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33129844

RESUMO

BACKGROUND & AIMS: Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. METHODS: Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. RESULTS: When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1ß mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8+ T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. CONCLUSIONS: In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.


Assuntos
Infecções por Helicobacter/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/imunologia , Administração Oral , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrinas/genética , Infecções por Helicobacter/induzido quimicamente , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Helicobacter felis/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Metilnitrosoureia/administração & dosagem , Camundongos , Camundongos Knockout , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/microbiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/microbiologia , Microambiente Tumoral/imunologia
15.
Gut ; 70(2): 330-341, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32393543

RESUMO

OBJECTIVE: Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1ß (IL-1ß) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1ß and chronic pancreatitis might contribute to PDAC progression. DESIGN: We crossed LSL-Kras +/G12D;Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1ß to generate KC-IL1ß mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples. RESULTS: KC-IL1ß mice developed PDAC with liver metastases. IL-1ß treatment increased Kras+/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1ß pancreata. Adoptive transfer of B lymphocytes from KC-IL1ß mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1ß mice. B cells isolated from KC-IL1ß mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8+ T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1ß pancreata, and depletion of IL-35 decreased the number of PD-L1+ B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival. CONCLUSION: We show here that IL-1ß promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.


Assuntos
Linfócitos B/imunologia , Carcinoma Ductal Pancreático/etiologia , Tolerância Imunológica/imunologia , Neoplasias Pancreáticas/etiologia , Pancreatite/complicações , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Citometria de Fluxo , Interleucina-1beta/efeitos adversos , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/imunologia , Pancreatite/etiologia , Pancreatite/imunologia
16.
Gut ; 70(4): 654-665, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32709613

RESUMO

BACKGROUND AND AIMS: The gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation. METHODS: We used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with Helicobacter felis. We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells. RESULTS: In both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing. CONCLUSION: Gastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.

17.
Gastroenterology ; 160(4): 1224-1239.e30, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33197448

RESUMO

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. METHODS: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. RESULTS: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor ß and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. CONCLUSIONS: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Colorretais/patologia , Imunoglobulinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Progressão da Doença , Feminino , Hepatócitos/metabolismo , Humanos , Imunoglobulinas/genética , Estimativa de Kaplan-Meier , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais , Microambiente Tumoral , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Biomedicines ; 8(10)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066474

RESUMO

In Asia, the incidences of Helicobacter pylori infection and gastric cancer are high, but their association with autoimmune gastritis (AIG) is unclear. This was a retrospective cohort study of patients endoscopically diagnosed with chronic gastritis between 2005 and 2017. AIG was diagnosed according to anti-parietal cell antibody positivity. Laboratory, histological findings, and gastric cancer incidence were compared between AIG and non-AIG patients. The AIG group had more females and a higher rate of thyroid disease. Serum levels of gastrin were significantly higher in AIG patients (mean 1412 and 353 pg/mL, p < 0.001). The endoscopic findings included a significantly higher percentage of corpus-dominant atrophy in AIG (31.67%) than in non-AIG (7.04%) patients (p < 0.001). Clusters of ECL cells were observed in 28% of AIG patients and 7% of non-AIG patients (p = 0.032). The cumulative incidence of gastric cancer at 5 and 10 years was 0% and 0.03% in the AIG group and 0.03% and 0.05% in the non-AIG group, and no significant difference in gastric cancer incidence was observed. Despite significant differences in gastrin levels between AIG and non-AIG patients, there was no evidence of an impact of AIG on the incidence of gastric cancer.

19.
Cancer Genomics Proteomics ; 17(6): 695-705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33099471

RESUMO

BACKGROUND/AIM: The entire mechanisms by which epigenetic modifiers contribute to the development of pancreatic cancer remain unknown. Although the histone methyltransferase G9a is a promising target in human cancers, its role in pancreatic carcinogenesis has been under-studied. The aim of the study was to examine the role of G9a in pancreatic carcinogenesis by a gene-targeting mouse model. MATERIALS AND METHODS: We established pancreas-specific G9aflox/flox mice and crossed them with Ptf1aCre/; KrasG12D/+ (KC) mice, which spontaneously develop pancreatic cancer. The phenotypes of the resulting KC mice with G9a deletion were examined. We analyzed transcriptomic data by microarray and genome-wide chromatin accessibility by transposase-accessible chromatin using sequencing. We established pancreatic organoids from KC mice. RESULTS: G9a deficiency impaired the progression of pancreatic intraepithelial neoplasia (PanIN) and prolonged the survival of KC mice. The number of phosphorylated Erk-positive cells and Dclk1-positive cells, which are reported to be essential for the progression of PanIN, were decreased by G9a deletion. UNC0638, an inhibitor of G9a, suppressed the growth of organoids and increased global chromatin accessibility, especially around the regions including the protein phosphatase 2A genes. CONCLUSION: Thus, our study suggested the functional interaction of G9a, Dclk1 and Mapk pathway in the Kras-driven pancreatic carcinogenesis. The inhibition of G9a may suppress the initiation of oncogenic Kras-driven pancreatic carcinogenesis.


Assuntos
Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/fisiologia , Mutação , Neoplasias Pancreáticas/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Carcinogênese/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
20.
Helicobacter ; 25(5): e12719, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32602161

RESUMO

BACKGROUND: A small proportion of Helicobacter pylori-infected individuals in Japan suffer failure of eradication therapy with third-line regimens containing the potent acid suppressor, vonoprazan, and a quinolone. OBJECTIVES: This prospective study evaluated the efficacy and safety of rifabutin-based triple therapy with vonoprazan for refractory H pylori infection. METHODS: Patients who failed H pylori eradication by clarithromycin-based first-line, metronidazole-based second-line, and sitafloxacin-based third-line therapies were recruited. After obtaining informed consent, patients received eradication therapy with vonoprazan (20 mg), amoxicillin (750 mg), and rifabutin (150 mg) twice daily for 10 days. Eradication was confirmed by a negative H pylori stool antigen or urea breath test at least 8 weeks after the end of therapy. RESULTS: Nineteen patients were included in the study. All of the patients completed the course of medication. Eradication of H pylori was confirmed in all of the patients (19/19; 100%, 95% confidence interval; 83-100%). The most common adverse event was soft stool/diarrhea (4/19, 21%). No severe adverse event was observed. CONCLUSIONS: Ten-day rifabutin with amoxicillin and vonoprazan triple therapy appears to be effective and safe for refractory H pylori infections. However, considering the recent publications showing high eradication rates with vonoprazan amoxicillin dual therapy, confirmation will require future studies comparing our new therapy with vonoprazan-amoxicillin dual with similar doses and duration and with vonoprazan-rifabutin dual therapy.


Assuntos
Amoxicilina , Antibacterianos , Infecções por Helicobacter/tratamento farmacológico , Pirróis , Rifabutina , Sulfonamidas , Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Quimioterapia Combinada , Feminino , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Rifabutina/administração & dosagem , Sulfonamidas/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...