Publications by authors named "Yoku Hayakawa"

100 Publications

Detection of Premalignant Gastrointestinal Lesions Using Surface-Enhanced Resonance Raman Scattering-Nanoparticle Endoscopy.

ACS Nano 2019 02 4;13(2):1354-1364. Epub 2019 Feb 4.

Department of Radiology , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.

Cancers of the gastrointestinal (GI) tract are among the most frequent and most lethal cancers worldwide. An important reason for this high mortality is that early disease is typically asymptomatic, and patients often present with advanced, incurable disease. Even in high-risk patients who routinely undergo endoscopic screening, lesions can be missed due to their small size or subtle appearance. Thus, current imaging approaches lack the sensitivity and specificity to accurately detect incipient GI tract cancers. Here we report our finding that a single dose of a high-sensitivity surface-enhanced resonance Raman scattering nanoparticle (SERRS-NP) enables reliable detection of precancerous GI lesions in animal models that closely mimic disease development in humans. Some of these animal models have not been used previously to evaluate imaging probes for early cancer detection. The studies were performed using a commercial Raman imaging system, a newly developed mouse Raman endoscope, and finally a clinically applicable Raman endoscope for larger animal studies. We show that this SERRS-NP-based approach enables robust detection of small, premalignant lesions in animal models that faithfully recapitulate human esophageal, gastric, and colorectal tumorigenesis. This method holds promise for much earlier detection of GI cancers than currently possible and could lead therefore to marked reduction of morbidity and mortality of these tumor types.
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http://dx.doi.org/10.1021/acsnano.8b06808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428194PMC
February 2019

BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice.

Gastroenterology 2019 03 15;156(4):1066-1081.e16. Epub 2018 Nov 15.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York. Electronic address:

Background & Aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated.

Methods: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc, LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set.

Results: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15 cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15 secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15 secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15 precursors toward those of ISCs. Bhlha15 enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate-induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon.

Conclusions: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs.
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http://dx.doi.org/10.1053/j.gastro.2018.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409180PMC
March 2019

Gastric Stem Cell and Cellular Origin of Cancer.

Biomedicines 2018 Oct 31;6(4). Epub 2018 Oct 31.

Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 1138655, Japan.

Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that + cells in the gut are the origin of gastrointestinal cancers. Reserve or facultative stem or progenitor cells with the ability to convert to + cells following injury have also been identified. Unlike the intestine, where + cells at the crypt base act as active stem cells, the stomach may contain unique stem cell populations, since gastric + cells seem to behave as a reserve rather than active stem cells, both in the corpus and in the antral glands. Gastrointestinal stem cells are supported by a specific microenvironment, the stem cell niche, which also promotes tumorigenesis. This review focuses on stem cell markers in the gut and their supporting niche factors. It also discusses the molecular mechanisms that regulate stem cell function and tumorigenesis.
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http://dx.doi.org/10.3390/biomedicines6040100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315982PMC
October 2018

Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness.

Cancer Discov 2018 11 5;8(11):1458-1473. Epub 2018 Sep 5.

Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL- ;-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL- ;LSL- ;-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Subdiaphragmatic vagotomy or knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214763PMC
November 2018

Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium.

J Pathol 2019 01 27;247(1):35-47. Epub 2018 Nov 27.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal-type gastric cancer, and Cdh1 mutation is associated with diffuse-type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1-Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, Tff1-Cre-mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of Tff1-Cre;LSL-Kras mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue-positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide-expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus-derived organoids from Tff1-Cre;LSL-Kras mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. Tff1-Cre;Pten mice displayed similar changes to those seen in Tff1-Cre;LSL-Kras mice, both with aberrant ERK activation within 3 months. In contrast, Tff1-Cre;Cdh1 mice initially showed signet ring-like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1-Cre;Cdh1 mice was completely replaced by squamous epithelium which expanded from the forestomach. Tff1-Cre mice offer an additional useful tool for studying gastric carcinogenesis both in vivo and in vitro. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5163DOI Listing
January 2019

Role of warfarin as a predictor of recurrent bleeding after negative small-bowel capsule endoscopy.

Gastrointest Endosc 2018 09;88(3):574-574.e2

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.gie.2018.04.2344DOI Listing
September 2018

The Tuft Cell-ILC2 Circuit Integrates Intestinal Defense and Homeostasis.

Cell 2018 07;174(2):251-253

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address:

The intestinal response to helminth infection is mediated by a recently established type 2 immune circuit that consists of intestinal tuft cells and type 2 innate lymphoid cells (ILC2s). Schneider et al. have discovered that tuft cells sense succinate fermented by Tritrichomonas via GPR91 to drive the IL-25-ILC2-IL-13-dependent immune circuit and intestinal remodeling.
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http://dx.doi.org/10.1016/j.cell.2018.06.037DOI Listing
July 2018

Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease.

J Crohns Colitis 2018 Nov;12(10):1219-1231

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Aims: Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease [IBD], and TGF-β signalling impairment in mononuclear phagocytes [MPs] causes murine colitis with goblet cell depletion. Here, we examined an organoid-MP co-culture system to study the role of MPs in intestinal epithelial differentiation and homeostasis.

Methods: Intestinal organoids were co-cultured with lamina propria leukocytes and bone marrow-derived dendritic cells [BMDCs] from CD11c-cre Tgfbr2fl/fl mice. Organoid-MP adhesive interactions were evaluated by microscopy, RT-PCR, and flow cytometry. Murine colitis models (dextran sodium sulphate [DSS], CD11c-cre Tgfbr2fl/fl, T-cell-transfer) were used for histological and immunohistochemical analysis. Anti-E-cadherin antibody treatment or CD11c+-cell-specific CDH1 gene deletion were performed for E-cadherin neutralization or knockout. Colonic biopsies from patients with ulcerative colitis were analysed by flow cytometry.

Results: Intestinal organoids co-cultured with CD11c+ lamina propria leukocytes or BMDCs from CD11c-cre Tgfbr2fl/fl mice showed morphological changes and goblet cell depletion with Notch signal activation, analogous to CD11c-cre Tgfbr2fl/fl colitis. E-cadherin was upregulated in CD11c+ MPs, especially CX3CR1+CCR2+ monocytes, of CD11c-cre Tgfbr2fl/fl mice. E-cadherin-mediated BMDC adhesion promoted Notch activation and cystic changes in organoids. Anti-E-cadherin antibody treatment attenuated colitis in CD11c-cre Tgfbr2fl/fl and T-cell-transferred mice. In addition, E-cadherin deletion in CD11c+ cells attenuated colitis in both CD11c-cre Tgfbr2fl/fl and DSS-treated mice. In patients with ulcerative colitis, E-cadherin expressed by intestinal CD11c+ leukocytes was enhanced compared with that in healthy controls.

Conclusions: E-cadherin-mediated MP-epithelium adhesion is associated with the development of colitis, and blocking these adhesions may have therapeutic potential for IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjy088DOI Listing
November 2018

Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis.

Gut 2019 04 17;68(4):684-692. Epub 2018 Apr 17.

School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Objective: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, , and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein.

Design: We use organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair.

Results: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting.

Conclusion: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.
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http://dx.doi.org/10.1136/gutjnl-2017-315920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192855PMC
April 2019

Efficacy of Vonoprazan for Gastroesophageal Reflux Symptoms in Patients with Proton Pump Inhibitor-resistant Non-erosive Reflux Disease.

Intern Med 2018 Sep 30;57(17):2443-2450. Epub 2018 Mar 30.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.

Objective Clinically, patients with proton pomp inhibitor (PPI)-resistant gastroesophageal reflux disease (GERD) are very challenging to treat. The aim of this study was to determine the rates of symptom relief and adverse events among PPI-resistant GERD patients that changed their therapy from a PPI to vonoprazan. Methods Patients with severe gastroesophageal reflux symptoms (total GERD-Q score ≥8) without endoscopic findings of mucosal breaks who changed their medication from a PPI to vonoprazan during a 12-week period from 2015 to 2016 at 2 hospitals were selected. The primary outcome was the self-reported relief of gastroesophageal reflux symptoms. The odds ratio (OR) for the improvement of symptoms was calculated based on an exact binomial distribution using a matched-pair analysis. The secondary outcome was the GERD-Q score and adverse events. Results Twenty-six patients (6 men) with a mean age of 67.5 years were analyzed. After the therapy was changed from a PPI to vonoprazan, 18 patients (69.2%) reported an improvement, 6 (23.1%) reported no change, and 2 (7.7%) reported an exacerbation of symptoms. A change in therapy was significantly associated with improved self-reported symptoms (OR 9.0, p<0.001). The mean total GERD-Q score during vonoprazan treatment was significantly lower than that during PPI therapy (11.96 vs. 8.92). There were no significant differences in the incidence of adverse events between the therapies. Conclusion Changing the medication from a PPI to vonoprazan was significantly associated with an improvement in gastroesophageal reflux symptoms. Vonoprazan is one of the most promising treatment options for patients with PPI-resistant GERD.
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http://dx.doi.org/10.2169/internalmedicine.0492-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172555PMC
September 2018

Sessile serrated adenoma detection rate is correlated with adenoma detection rate.

World J Gastrointest Oncol 2018 Mar;10(3):82-90

Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.

Aim: To investigated the association between adenoma detection rate (ADR) and sessile serrated ADR (SSADR) and significant predictors for sessile serrated adenomas (SSA) detection.

Methods: This study is a retrospective, single-center analysis. Total colonoscopies performed by the gastroenterologists at the University of Tokyo Hospital between January and December 2014 were retrospectively identified. Polyps were classified as low-grade or high-grade adenoma, cancer, SSA, or SSA with cytological dysplasia, and the prevalence of each type of polyp was investigated. Predictors of adenoma and SSA detection were examined using logistic generalized estimating equation models. The association between ADR and SSADR for each gastroenterologist was investigated by calculating a correlation coefficient weighted by the number of each gastroenterologist's examination.

Results: A total of 3691 colonoscopies performed by 35 gastroenterologists were assessed. Overall, 978 (26.5%) low- and 84 (2.2%) high-grade adenomas, 81 (2.2%) cancers, 66 (1.8%) SSAs, and 2 (0.1%) SSAs with cytological dysplasia were detected. Overall ADR was 29.5% (men 33.2%, women 23.8%) and overall SSADR was 1.8% (men 1.7%, women 2.1%). In addition, 672 low-grade adenomas (68.8% of all the detected low-grade adenomas), 58 (69.9%) high-grade adenomas, 29 (34.5%) cancers, 52 (78.8%) SSAs, and 2 (100%) SSAs with cytological dysplasia were found in the proximal colon. Adenoma detection was the only significant predictor of SSA detection (adjusted OR: 2.53, 95%CI: 1.53-4.20; < 0.001). The correlation coefficient between ADR and SSADR weighted by the number of each gastroenterologist's examinations was 0.606 ( < 0.001).

Conclusion: Our results demonstrated that ADR is correlated to SSADR. In addition, patients with adenomas had a higher prevalence of SSAs than those without adenomas.
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http://dx.doi.org/10.4251/wjgo.v10.i3.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852399PMC
March 2018

Distinct Chemopreventive Effects of Aspirin in Diffuse and Intestinal-Type Gastric Cancer.

Cancer Prev Res (Phila) 2018 05 16;11(5):279-286. Epub 2018 Feb 16.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Although aspirin/NSAIDs may have potential preventive effects on several cancers, it remains unclear on gastric cancer. The purpose of this study is to compare the risk of developing gastric cancer and the histologic changes of intestinal metaplasia and neutrophil infiltration, between aspirin/NSAID users and nonusers. Using an electronic endoscopy database in two hospitals from 1996 to 2017, we analyzed the data from patients with chronic gastritis who received aspirin or NSAIDs prior to upper gastrointestinal endoscopy. One-to-one propensity score matching was performed to compare the proportion of gastric cancer, intestinal metaplasia, and neutrophil infiltration between these drug users and nonusers. We analyzed 2,082 aspirin users and 2,082 nonusers as well as 898 NSAID users and 898 nonusers. Six diffuse-type and 19 intestinal-type gastric cancer, 1,243 intestinal metaplasia, and 1,503 neutrophil infiltration patients were identified. The proportion of diffuse-type gastric cancer (0.05%) was 80% lower in aspirin users compared with the nonusers (0.24%), and there was no case of diffuse-type cancer in patients who took aspirin for more than 2 years. In contrast, intestinal-type gastric cancer incidence was significantly higher in aspirin users (0.72%) compared with nonusers (0.14%). No significant differences in the incidence of gastric cancer were found between NSAID use and nonusers. NSAID use was significantly associated with decreased proportion of neutrophil infiltration compared with nonusers. Aspirin may have distinct effects between intestinal-type and diffuse-type gastric cancer development. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0276DOI Listing
May 2018

Mature gastric chief cells are not required for the development of metaplasia.

Am J Physiol Gastrointest Liver Physiol 2018 05 18;314(5):G583-G596. Epub 2018 Jan 18.

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo , Tokyo , Japan.

During human gastric carcinogenesis, intestinal metaplasia is frequently seen in the atrophic stomach. In mice, a distinct type of metaplasia known as spasmolytic polypeptide-expressing metaplasia (SPEM) is found in several inflammatory and genetically engineered models. Given the diversity of long- and short-term models of mouse SPEM, it remains unclear whether all models have a shared or distinct molecular mechanism. The origin of SPEM in mice is presently under debate. It is postulated that stem or progenitor cells acquire genetic alterations that then supply metaplastic cell clones, whereas the possibility of transdifferentiation or dedifferentiation from mature gastric chief cells has also been suggested. In this study, we report that loss of chief cells was sufficient to induce short-term regenerative SPEM-like lesions that originated from chief cell precursors in the gastric neck region. Furthermore, Lgr5 mature chief cells failed to contribute to both short- and long-term metaplasia, whereas isthmus stem and progenitor cells efficiently contributed to long-term metaplasia. Interestingly, multiple administrations of high-dose pulsed tamoxifen induced expansion of Lgr5 expression and Lgr5-CreERT recombination within the isthmus progenitors apart from basal chief cells. Thus we conclude that short-term SPEM represents a regenerative process arising from neck progenitors following chief cell loss, whereas true long-term SPEM originates from isthmus progenitors. Mature gastric chief cells may be dispensable for SPEM development. NEW & NOTEWORTHY Recently, dedifferentiation ability in gastric chief cells during metaplasia development has been proposed. Our findings reveal that lesions that were thought to be acute metaplasia in fact represent normal regeneration supplied from neck lineage and that isthmus stem/progenitors are more responsible for sustained metaplastic changes. Cellular plasticity in gastric chief cells may be more limited than recently highlighted.
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http://dx.doi.org/10.1152/ajpgi.00351.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732738PMC
May 2018

CXCR4-expressing progenitors in the gastric antrum contribute to gastric cancer development.

Oncotarget 2017 Dec 10;8(67):111012-111025. Epub 2017 Nov 10.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.

was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express . The relevance of expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using -CreERT mice, we revealed that antral cells, distinct from the population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above or CCK2R cells. antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4 epithelial cells as well as the Cxcl12 perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target.
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http://dx.doi.org/10.18632/oncotarget.22451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762301PMC
December 2017

Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment for : a retrospective cohort analysis.

Gut 2018 10 22;67(10):1908-1910. Epub 2017 Dec 22.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1136/gutjnl-2017-315710DOI Listing
October 2018

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

Cancer Cell 2018 01 14;33(1):75-90.e7. Epub 2017 Dec 14.

Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address:

Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras;LSL-Trp53;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
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http://dx.doi.org/10.1016/j.ccell.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760435PMC
January 2018

Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop.

Cell Stem Cell 2017 Dec 30;21(6):747-760.e7. Epub 2017 Nov 30.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, University of Western Ontario, London, ON N6A 5W9, Canada.

Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via lipopolysaccharide (LPS) treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically primed MB-HSCs to enforce homeostasis.
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http://dx.doi.org/10.1016/j.stem.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975960PMC
December 2017

Nerves switch on angiogenic metabolism.

Science 2017 10;358(6361):305-306

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA.

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http://dx.doi.org/10.1126/science.aaq0365DOI Listing
October 2017

Colonoscopy reduces colorectal cancer mortality: A multicenter, long-term, colonoscopy-based cohort study.

PLoS One 2017 28;12(9):e0185294. Epub 2017 Sep 28.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: There are limited colonoscopy-based cohort data concerning the effectiveness of colonoscopy in reducing colorectal cancer deaths. The aim of this study was to clarify whether colonoscopy reduces colorectal cancer mortality.

Methods: A cohort of 18,816 patients who underwent colonoscopy without a diagnosis of colorectal cancer between 2001 and 2010 at high colonoscopy procedure volume centers was selected. Patient characteristics and colonoscopy findings were assessed. The main endpoint was colorectal cancer death (all, right-sided, and left-sided cancers), and data were censored at the time of the final visit or the final colonoscopy. The standardized all colorectal, colon, and rectal cancer mortality rates were estimated with reference to those of the general Japanese population. Additional outcome was all- cause death and the standardized all-cause mortality rate was also estimated.

Results: The total observed person-year mortality for colorectal cancer was 67,119. Of these, 4, 3, and 1 patients died from colorectal, colon, and rectal cancers, respectively; these values were significantly lower than the number of expected deaths in the general population, estimated to be 53.1, 34.0, and 19.1, respectively. The standardized mortalities for all colorectal, colon, and rectal cancers were 0.08 (95% confidence interval (CI), 0.02-0.17), 0.09 (95% CI, 0.02-0.22), and 0.05 (95% CI, 0.0002-0.21), respectively. There were 586 all-cause deaths (3.11%) during the observation period. The standardized all-cause mortality ratios were 0.22 (95% CI, 0.206-0.23).

Conclusions: The colorectal cancer mortality of patients who received colonoscopy without colorectal cancer diagnosis decreased significantly compared with that of individuals in the general population. These results were compatible even in patients with right-sided colon cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185294PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619740PMC
October 2017

Metaplasia in the Stomach-Precursor of Gastric Cancer?

Int J Mol Sci 2017 Sep 27;18(10). Epub 2017 Sep 27.

Graduate School of Medicine, Department of Gastroenterology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Despite a significant decrease in the incidence of gastric cancer in Western countries over the past century, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Most human gastric cancers develop after long-term infection via the Correa pathway: the progression is from gastritis, atrophy, intestinal metaplasia, dysplasia, to cancer. However, it remains unclear whether metaplasia is a direct precursor of gastric cancer or merely a marker of high cancer risk. Here, we review human studies on the relationship between metaplasia and cancer in the stomach, data from mouse models of metaplasia regarding the mechanism of metaplasia development, and the cellular responses induced by infection.
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http://dx.doi.org/10.3390/ijms18102063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666745PMC
September 2017

Dclk1-expressing tuft cells: critical modulators of the intestinal niche?

Am J Physiol Gastrointest Liver Physiol 2017 Oct 6;313(4):G285-G299. Epub 2017 Jul 6.

II. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;

-expressing tuft cells constitute a unique intestinal epithelial lineage that is distinct from enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. Tuft cells express taste-related receptors and distinct transcription factors and interact closely with the enteric nervous system, suggesting a chemosensory cell lineage. In addition, recent work has shown that tuft cells interact closely with cells of the immune system, with a critical role in the cellular regulatory network governing responses to luminal parasites. Importantly, ablation of tuft cells severely impairs epithelial proliferation and tissue regeneration after injury, implicating tuft cells in the modulation of epithelial stem/progenitor function. Finally, tuft cells expand during chronic inflammation and in preneoplastic tissues, suggesting a possible early role in inflammation-associated tumorigenesis. Hence, we outline and discuss emerging evidence that strongly supports tuft cells as key regulatory cells in the complex network of the intestinal microenvironment.
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http://dx.doi.org/10.1152/ajpgi.00073.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668570PMC
October 2017

Prevalence of -positive in Japanese patients with or without colorectal cancer.

Gut Pathog 2017 12;9:35. Epub 2017 Jun 12.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan.

Background: Recent studies show that some strains possessing a gene cluster named the island might have a causative role in the development of human colorectal cancer (CRC). In several reports from Europe, they are found more prevalently in colon tissue specimens derived from CRC patients compared to those from controls. In this study we sought to clarify the difference in prevalence between CRC patients and non-CRC controls in the Japanese population, by using non-invasive sample collection technique during colonoscopy.

Methods: Colonic lavage samples were collected during diagnostic colonoscopy, and bacterial DNA within each sample was extracted. Fecal DNA samples were then examined for island genes using conventional qualitative PCR and real-time quantitative PCR. In some patients biopsy samples were also collected in the same session of colonoscopy, and the correlation between the status of the colonic lavage sample and the biopsy sample of the same patients was evaluated.

Results: Twelve out of thirteen patients (92%) showed the same status by colonic lavage sample and biopsy sample, suggesting the usefulness of colonic lavage samples as a surrogate for biopsy samples. A total of 98 colonic lavage samples were collected, which included 35 from CRC patients, 37 from adenoma patients, and 26 from controls. The -positive bacterial DNA was detected in 43, 51, and 46% of colonic lavage samples from CRC, adenoma, and control patients, respectively, and there was no significant difference among diseases. Real-time quantitative PCR showed no significant difference in the relative concentrations of -positive bacterial DNA among diseases. Age, gender, location of CRC, CRC staging, or - gene status was not associated with prevalence.

Conclusions: Although the method of collecting fecal DNA from colonic lavage samples was safe and technically feasible, factors other than -positive bacteria appear to play more important roles in CRC development in this cohort.
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http://dx.doi.org/10.1186/s13099-017-0185-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468999PMC
June 2017

Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus.

Cell Mol Gastroenterol Hepatol 2017 Jul 6;4(1):89-94. Epub 2017 Mar 6.

Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University Medical Center, New York, New York.

The acquisition of genetic/epigenetic mutations in long-lived gastrointestinal stem cells leads to the development of cancer, as well as precancerous lesions such as metaplasia and dysplasia. In the proximal stomach corpus, this model of progression from stem cells has been supported by studies in mice and human beings, showing abundant proliferation in the isthmus and clonal expansion of mutated cells from the stem cell region. An alternative theory proposes that gastric metaplasia arises from mature differentiated chief cells. Despite reports of low levels of proliferation in chief cells in acute injury models, there is little evidence for reprogramming of chief cells into long-lived stem cells that continuously supply progeny over time. Critical flaws in the chief cell transdifferentiation theory include the definition of acute SPEM, the chief cell-damaging effect of chemical reagents, and the specificity of chief cell lineage tracing. In contrast, there is now strong evidence regarding the stem cell origins of gastric metaplasia that refutes the transdifferentiation theory. Here, we briefly review the history and definition of gastric metaplasia, and outline in detail the evidence that supports the stem cell origin of metaplasia.
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http://dx.doi.org/10.1016/j.jcmgh.2017.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440357PMC
July 2017

Isthmus Progenitors, Not Chief Cells, Are the Likely Origin of Metaplasia in eR1-CreERT; LSL-Kras Mice.

Gastroenterology 2017 06 4;152(8):2078-2079. Epub 2017 May 4.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.

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http://dx.doi.org/10.1053/j.gastro.2017.02.043DOI Listing
June 2017

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

Cell Mol Gastroenterol Hepatol 2017 May 20;3(3):331-338. Epub 2017 Feb 20.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.

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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http://dx.doi.org/10.1016/j.jcmgh.2017.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404024PMC
May 2017

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands.

Proc Natl Acad Sci U S A 2017 05 24;114(19):E3806-E3815. Epub 2017 Apr 24.

Department of Gastroenterology, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.

The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras- and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing , , and mice ( ). However, mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, mice were crossed with mice ( ). Surprisingly, mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.
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http://dx.doi.org/10.1073/pnas.1619416114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441746PMC
May 2017

Association between gastric cancer and the Kyoto classification of gastritis.

J Gastroenterol Hepatol 2017 Sep;32(9):1581-1586

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Aim: Histological gastritis is associated with gastric cancer, but its diagnosis requires biopsy. Many classifications of endoscopic gastritis are available, but not all are useful for risk stratification of gastric cancer. The Kyoto Classification of Gastritis was proposed at the 85th Congress of the Japan Gastroenterological Endoscopy Society. This cross-sectional study evaluated the usefulness of the Kyoto Classification of Gastritis for risk stratification of gastric cancer.

Methods: From August 2013 to September 2014, esophagogastroduodenoscopy was performed and the gastric findings evaluated according to the Kyoto Classification of Gastritis in a total of 4062 patients. The following five endoscopic findings were selected based on previous reports: atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness.

Results: A total of 3392 patients (1746 [51%] men and 1646 [49%] women) were analyzed. Among them, 107 gastric cancers were diagnosed. Atrophy was found in 2585 (78%) and intestinal metaplasia in 924 (27%). Enlarged folds, nodularity, and diffuse redness were found in 197 (5.8%), 22 (0.6%), and 573 (17%), respectively. In univariate analyses, the severity of atrophy, intestinal metaplasia, diffuse redness, age, and male sex were associated with gastric cancer. In a multivariate analysis, atrophy and male sex were found to be independent risk factors. Younger age and severe atrophy were determined to be associated with diffuse-type gastric cancer.

Conclusion: Endoscopic detection of atrophy was associated with the risk of gastric cancer. Thus, patients with severe atrophy should be examined carefully and may require intensive follow-up.
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http://dx.doi.org/10.1111/jgh.13764DOI Listing
September 2017

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.

Cancer Cell 2017 01 15;31(1):21-34. Epub 2016 Dec 15.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.

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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http://dx.doi.org/10.1016/j.ccell.2016.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225031PMC
January 2017
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