Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis.

KANAI Takanori

Cell (Cell) 174 ( 4 ) 856 - 869.e17 2018

ISSN 00928674

© 2018 Elsevier Inc. Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers. Generation and analysis of a human gastric cancer organoid bank reveal insights into molecular features underlying diverse histopathological subtypes and tumor independence from Wnt signals.

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Innate lymphoid cells in organ fibrosis. Cytokine Growth Factor Rev

KANAI Takanori

Cytokine Growth Factor Rev 2018

Correction: Clinical utility of novel ultrathin single-balloon enteroscopy: a feasibility study

KANAI Takanori

Endoscopy 2018

Management of challenging immune-related gastrointestinal adverse events associated with immune checkpoint inhibitors.

KANAI Takanori

Future Oncol (Future Oncology) 14 ( 30 ) 3187 - 3198 2018

ISSN 14796694

© 2018 Future Medicine Ltd. Immune-related gastrointestinal toxicities (irGI) are well-known adverse events (AEs) with immune checkpoint inhibitors. The aim of this review was to present clinical data from 82 cases to provide information to clinicians who face real-world challenges among their patients with irGI AEs. The findings of this review support the use of the current management guidelines. By analyzing the treatment courses and outcomes of all cases identified, our review recommends that recurrent cases be treated carefully regardless of the grade of diarrhea at the onset of events. Earlier gastroenterology consultation and computed tomography/endoscopy diagnosis are essential, especially when an irGI AE recurs or worsens during steroid tapering. We would also suggest earlier decision to add immunosuppressant agents, particularly for recurrent cases.

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Efficacy of Therapeutic Intervention for Patients With an Ulcerative Colitis Mayo Endoscopic Score of 1.

KANAI Takanori

Inflamm Bowel Dis (Inflammatory Bowel Diseases) 25 ( 4 ) 782 - 788 2018

ISSN 10780998

© 2018 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions. Background Mucosal healing (MH) is proposed as a therapeutic target for ulcerative colitis (UC). Recent studies have indicated that the rate of clinical relapse in patients with a Mayo endoscopic score (MES) of 1 is higher than that of patients with an MES of 0. However, no study has yet investigated whether therapeutic intervention prevents clinical relapse in patients with an MES of 1. Methods Patients with UC with an MES of 1 and partial Mayo score ≤2 were included in this study. All patients were followed from first colonoscopy (CS) until follow-up CS. Differences in the rate of clinical relapse (requiring additional treatment for UC) or endoscopic exacerbation (MES ≥2 and proximal extension) were compared between the therapeutic intervention (immediately after first CS) group and the nontherapeutic intervention group; risk factors for relapse were also assessed. Results Among 1523 patients with UC who underwent CS between 2013 and 2016, 220 patients were included in this study. The rate of clinical relapse (P = 0.005) and endoscopic exacerbation (P = 0.11) in patients with therapeutic intervention was lower than that in patients without therapeutic intervention. Multivariable analysis indicated that absence of therapeutic intervention (P = 0.001 for clinical relapse, P = 0.050 for endoscopic exacerbation) and a higher Ulcerative Colitis Endoscopic Index of Severity vascular pattern score immediately after first CS (P = 0.021 for clinical relapse, P = 0.019 for endoscopic exacerbation) were risk factors for both clinical relapse and endoscopic exacerbation. Conclusions Therapeutic intervention for patients with UC with an MES of 1 might prevent disease relapse.

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Factors predicting the therapeutic response to infliximab during maintenance therapy in Japanese patients with Crohn's disease

KANAI Takanori

PLoS One (PLoS ONE) 13 ( 10 ) 2018

© 2018 Hsieh et al. Since anti-tumor necrosis factor (TNF)-α agents (TNF-α inhibitors) induce both clinical response and remission in patients with moderate to severe inflammatory bowel disease (IBD), the use of anti-TNF therapies has fundamentally changed the approach to treatment for patients with IBD. Infliximab (IFX) is a TNF-α inhibitor approved for the induction and remission of Crohn's disease (CD). However, even among patients who initially demonstrate a clinical response to IFX therapy, secondary loss of response occurs, although the reason remains unknown. We therefore investigated predictive factors associated with the response to IFX in long-term maintenance treatment in Japanese CD patients. Eight types of single-nucleotide polymorphisms (SNPs) were investigated using the real-time PCR method, and patient characteristics were collected from the electronic medical records. The Crohn's Disease Activity Index criteria were used as the response to IFX therapy. The observation period was 1 year after IFX had been administered for more than 1 year. Associations between the IFX response and patient characteristics were evaluated using the multivariate logistic regression model. We studied 121 unrelated adult Japanese with CD treated for more than 1 year with IFX as outpatients at Keio University Hospital from November 1, 2014 to November 30, 2015. Among them, 71 were classified as in remisson. In multivariate analysis, patients with the TNF-α 857C>T C/C genotype, shorter disease duration, without double dosing, and combination treatment with an immunomodulator had higher remisson rates than those with the C/T or T/T genotype, longer disease duration, with double dosing, and no combination treatment with an immunomodulator. The response to IFX in Japanese CD patients may therefore be predicted by these 4 characteristics in actual clinical practice.

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Fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient with ulcerative colitis.

KANAI Takanori

Intest Res (Intestinal Research) 16 ( 1 ) 142 - 146 2018

ISSN 15989100

© 2018. Korean Association for the Study of Intestinal Diseases. Fecal microbiota transplantation (FMT) has been reported as a safe and effective therapy in patients with refractory and recurrent Clostridium difficile infection (CDI). FMT has also been reported as a promising therapy in patients with ulcerative colitis (UC). Both, CDI and UC, are believed to be caused by dysbiosis, such as altered compositions or decreased diversity of the intestinal microbiota. This report describes a patient with UC in remission with a second recurrent episode of CDI, who was treated with FMT. A single FMT performed via colonoscopy completely resolved the patient's diarrhea and eradicated C. difficile bacteriologically without any severe complications. Molecular biological analysis of the patient's fecal microbiota showed that FMT could dramatically change the altered composition of intestinal microbiota and restore its diversity. Despite the restoration of the intestinal microbiota, FMT could not prevent a relapse of UC in this patient. However, it improved the intestinal symptoms of CDI and could prevent further recurrences of CDI.

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Reconstruction of the Human Colon Epithelium In Vivo.

KANAI Takanori

Cell Stem Cell (Cell Stem Cell) 22 ( 2 ) 171 - 176.e5 2018

ISSN 19345909

© 2017 Elsevier Inc. Genetic lineage tracing has revealed that Lgr5 + murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium. Xenografted organoids formed crypt structures distinctively different from surrounding mouse crypts, reflecting their human origin. Lineage tracing using CRISPR-Cas9 to engineer an LGR5-CreER knockin allele demonstrated self-renewal and multipotency of LGR5 + CoSCs. In contrast to the rapidly cycling properties of mouse Lgr5 + CoSCs, human LGR5 + CoSCs were slow-cycling in vivo. This organoid-based orthotopic xenograft model enables investigation of the functional behaviors of human CoSCs in vivo, with potential therapeutic applications in regenerative medicine. Sugimoto et al. established an orthotopic xenotransplantation system for human normal colon organoids. Using LGR5-CreER knockin organoids for genetic lineage tracing, they demonstrated the self-renewal and multipotency of LGR5 + colon stem cells in mouse colon. Interestingly, human LGR5 + colon stem cells showed slower cycling than those of mice in vivo.

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Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.

KANAI Takanori

Cell Stem Cell (Cell Stem Cell) 22 ( 3 ) 454 - 467.e6 2018

ISSN 19345909

© 2017 Elsevier Inc. Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression. Sato and colleagues established a library of patient-derived pancreas cancer organoids and identified heterogeneous patterns of dependency on Wnt ligands among pancreas cancers. Biological and genetic analyses highlighted GATA6 as a mediator of the Wnt niche requirement, which links pancreatic tumor progression to independence from the stem cell niche.

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Methotrexate-associated Lymphoproliferative Disorder of the Stomach Presumed to Be Mucosa-associated Lymphoid Tissue Lymphoma

Ishigaki S., Masaoka T., Kameyama H., Kawaida M., Kameyama K., Mori T., Kanai T.

Internal medicine (Tokyo, Japan) (Internal medicine (Tokyo, Japan)) 57 ( 22 ) 3249 - 3254 2018

ISSN 09182918

The number of patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) is increasing. We describe a case of MTX-LPD of the stomach. After treatment with methotrexate for rheumatoid arthritis, the patient developed left cervical lymphadenopathy and an ulcerative lesion in the stomach, which was presumed to be a mucosa-associated lymphoid tissue (MALT) lymphoma. However, we suspected MTX-LPD, based on the clinical course and the positivity of in situ hybridization for the detection of the Epstein-Barr encoding region. After the cessation of MTX, the left cervical lymphadenopathy and the gastric lesion disappeared. This is first report of gastric MTX-LPD that was presumed to be MALT lymphoma.

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Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: An evidence-based review of therapies

Togasaki K., Sukawa Y., Kanai T., Takaishi H.

OncoTargets and Therapy (OncoTargets and Therapy) 11 8239 - 8250 2018

© 2018 Togasaki et al. Standard treatment options for patients with advanced gastric cancer (GC) offer limited efficacy and are associated with some toxicity, which necessitates the development of more effective therapies for improving the treatment outcomes for this disease. Immunotherapy involving immune checkpoint inhibitors (ICIs) which inhibit the programmed death 1 (PD-1)/ programmed death ligand 1 interaction has emerged as a new treatment option. Nivolumab, a human IgG4 monoclonal antibody inhibitor of PD-1, has demonstrated promising clinical activity and induced durable responses in patients with advanced GC. Nivolumab has recently been approved for treating patients with pretreated advanced GC in Japan. In the present review, we summarized current evidence of the clinical efficacy of ICIs in a variety of solid tumors and reported our experience in patients with GC who were treated with nivolumab and the interesting features that were observed in these cases. Certain ICI-specific clinical features such as pseudo-and hyper-progression of tumor and hyper-response to subsequent chemotherapy have been reported in several cancer types. Lastly, we discussed the present scenario regarding research on biomarkers for assessing the clinical benefits of ICI therapies.

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Analysis of sensitivity and cell death pathways mediated by anti-cancer drugs using three-dimensional culture system

Kinoshita T., Higuchi H., Ayano-Kabashima-Niibe, Sakai G., Hamamoto Y., Takaishi H., Kanai T.

International Journal of Cancer Research (International Journal of Cancer Research) 14 ( 1 ) 1 - 12 2018

ISSN 18119727

© 2018 Takeshi Kinoshita et al. Objective: The aim of this study was to evaluate the differences of cytotoxicity mediated by anti-cancer drugs between 2D and 3D culture conditions. Methodology: The colon cancer cell line HCT116 was cultured in 2D and 3D conditions. Anti-proliferation effects and cell death pathways of cytotoxic agents, i.e., SN-38 and multi-kinase inhibitors i.e., sorafenib were examined. Data was analyzed by Studentʼs t-test. Results: Although SN-38 induced significant apoptosis associated with caspase-3/7 activation in 2D condition, apoptosis and anti-proliferation effects of SN-38 dramatically diminished in 3D condition. In contrast, anti-proliferation effects mediated by sorafenib unchanged. Interestingly, sorafenib induced significant apoptosis in the cells locating in the center of the 3D spheroids, whereas it did not induce caspase activation in 2D condition. In addition, 2D culture with low glucose concentration, a model mimicking central condition of the spheroids, revealed the significant cell death with caspase activation by sorafenib. Conclusion: 3D culture system provide new findings regarding cytotoxicity of compounds which are not identified by the 2D culture.

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A male Korean who was diagnosed with chronic enteropathy associated with SLCO2A1 (CEAS): Case report with literature review

Sun X., Hosoe N., Miyanaga R., Kimura K., Mizuno S., Takabayashi K., Naganuma M., Niizeki H., Seki A., Ogata H., Kanai T.

BMJ Open Gastroenterology (BMJ Open Gastroenterology) 5 ( 1 ) 2018

Objective To further disseminate the nomenclature of chronic enteropathy associated with SLCO2A1 (CEAS), especially for physicians in China and Korea where the genetic feature of SLCO2A1 gene mutations related hypertrophic osteoarthropathy and pachydermia had been extensively studied. SLCO2A1 gene mutations related hypertrophic osteoarthropathy and pachydermia had been extensively studied. Design A case report with literature review of SLCO2A1 gene mutations-related disorders. Results A 38-year-old Korean presented to a tertiary hospital with dizziness, abdominal pain and melena. He had a positive faecal occult blood test on initial workup. Oesophagogastroduodenal endoscopy (OGD), colonoscopy and CT scan were unremarkable and showed no obvious cause for his melena. Capsule endoscope and roentgen barium studies were performed, revealing an erythematous mucosa with ulcers in the jejunum and stenosis to the jejunal-ileal junction. Next-generation sequencing was then performed and discovered point mutations of SLCO2A1 gene's seven exon (940+1 G>A) and 13 exon (1807 C>T) allele. This Korean patient with CEAS is the first documented case noted outside of the Japanese population. Conclusion CEAS is not uniquely found in Japanese individuals. There are lots of similarities between CEAS and primary hypertrophic osteoarthropathy, the two entity may just be the two sides of one same coin. International and multidisciplined efforts are required to further study this complicated disorder.

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Treatment strategy for inflammatory bowel disease with a focus on biologicals

Fukuda T., Naganuma M., Kanai T.

Journal of Japanese Society of Gastroenterology (Journal of Japanese Society of Gastroenterology) 115 ( 3 ) 272 - 282 2018

ISSN 04466586

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ß-(1,3)-Glucan derived from Candida albicans induces inflammatory cytokines from macrophages and lamina propria mononuclear cells derived from patients with Crohn's disease

Mori K., Naganuma M., Mizuno S., Suzuki H., Kitazume M.T., Shimamura K., Chiba S., Sugita A., Matsuoka K., Hisamatsu T., Kanai T.

Intestinal Research (Intestinal Research) 16 ( 3 ) 384 - 392 2018

ISSN 15989100

Background/Aims: Recent research has highlighted the importance of interactions between commensal fungi and intestinal inflammation. However, there are few studies investigating whether commensal fungi contribute to inflammation in patients with Crohn's disease (CD). The aim of this study is to investigate reveal interactions between commensal fungi and host immune cells in CD. Methods: CD14-positive monocytes were isolated from peripheral blood mononuclear cells from healthy human volunteers and then differentiated in the presence of macrophage colony-stimulating factor (M-CSF) (referred to as M-macrophages, M-MΦs) or M-CSF and interferon-γ (IFN-γ) (referred to as M-gamma macrophages, Mγ-Mϕs). Cytokine production by these in vitro differentiated macrophages in response to ß-(1,3)-glucan was analyzed by flow cytometry. Expression of Dectin-1 was examined using flow cytometry, western blotting, and quantitative reverse transcription-polymerase chain reaction. Cytokine production by in vitro differentiated macrophages in response to ß-(1,3)-glucan was measured in the presence of an anti-Dectin-1 receptor antagonist, anti-Syr, or an anti-Fas-1 antibody. Cytokine production by lamina propria mononuclear cells (LPMCs) derived from CD patients in response to ß-(1,3)-glucan was also analyzed. Results: Mγ-Mϕs produced a large amount of tumor necrosis factor-α (TNF-α) and interleukin-6 in response to ß-(1,3)-glucan. Dectin-1 expression was significantly higher in Mγ-Mϕs than in M-Mϕs. The increase in TNF-a production by Mγ-Mϕs stimulated with glucan was reversed by blocking Dectin-1, Syr or Fas-1. LPMCs derived from CD patients stimulated with ß-(1,3)-glucan produced significantly higher amount of TNF-α than LPMCs derived from UC patients. Conclusions: These results suggest that commensal fungal microbiota may contribute to the pathogenesis of CD by inducing macrophages-derived pro-inflammatory cytokines.

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Commensal Lactobacillus controls immune tolerance during acute liver injury in mice

Nakamoto N, Amiya T, Aoki R, Taniki N, Koda Y, Miyamoto K, Teratani T, Suzuki T, Chiba S, Chu PS, Hayashi A, Yamaguchi A, Shiba S, Miyake R, Katayama T, Suda W, Mikami Y, Kamada N, Ebinuma H, Saito H, Hattori M, Kanai T.

(Cell Rep. ) 21(5) 1215 - 1226 2017.10

Joint Work, Accepted

Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs) is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-β through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling.

Teratani T, Tomita K, Suzuki T, Furuhashi H, Irie R, Hida S, Okada Y, Kurihara C, Ebinuma H, Nakamoto N, Saito H, Hibi T, Miura S, Hokari R, Kanai T.

J Hepatol 67 ( 4 ) 780 - 790 2017.10

Joint Work, Accepted

BACKGROUND & AIMS:

Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA.

METHODS:

C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9-/-) mice and their Tlr9+/+ littermates were fed an HC diet for fourweeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses.

RESULTS:

The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs.

CONCLUSIONS:

HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen-induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism. Thus, free cholesterol accumulation, as an underlying metabolic factor, exacerbated the pathology of acetaminophen-induced liver injury through activation of the TLR9/inflammasome pathway.

Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Acetaminophen; Endosome; Free cholesterol; Inflammasome; Liver injury; Liver sinusoidal endothelial cell; Lysosome; Metabolic syndrome; Rab7; Toll-like receptor 9

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Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia though Overgrowth of Lactobacillus murinus in mice.

Hayashi A, Mikami Y, Miyamoto K, Kamada N, Sato T, Mizuno S, Naganuma M, Teratani T, Aoki R, Fukuda S, Suda W, Hattori M, Amagai M, Ohyama M, Kanai T.

Cell Rep. 20 ( 7 ) 1513 - 1524 2017.08

Joint Work, Accepted

Metabolism by the gut microbiota affects host physiology beyond the gastrointestinal tract. Here, we find that antibiotic-induced dysbiosis, in particular, overgrowth of Lactobacillus murinus (L. murinus), impaired gut metabolic function and led to the development of alopecia. While deprivation of dietary biotin per se did not affect skin physiology, its simultaneous treatment with vancomycin resulted in hair loss in specific pathogen-free (SPF) mice. Vancomycin treatment induced the accumulation of L. murinus in the gut, which consumes residual biotin and depletes available biotin in the gut. Consistently, L. murinus induced alopecia when monocolonized in germ-free mice fed a biotin-deficient diet. Supplementation of biotin can reverse established alopecia symptoms in the SPF condition, indicating that L. murinus plays a central role in the induction of hair loss via a biotin-dependent manner. Collectively, our results indicate that luminal metabolic alterations associated with gut dysbiosis and dietary modifications can compromise skin physiology.

Copyright © 2017. Published by Elsevier Inc.

Visualization and targeting of LGR5+ human colon cancer stem cells.

Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T.

Nature 545 ( 7653 ) 187 - 192 2017.05

Joint Work, Accepted

The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5+ CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.

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Single fecal microbiota transplantation failed to change intestinal microbiota and had limited effectiveness against ulcerative colitis in Japanese patients.

Mizuno S, Nanki K, Matsuoka K, Saigusa K, Ono K, Arai M, Sugimoto S, Kiyohara H, Nakashima M, Takeshita K, Naganuma M, Suda W, Hattori M, Kanai T.

Intest Res 1 68 - 74 2017.01

Joint Work, Accepted

BACKGROUND/AIMS:

Recent developments in analytical techniques including next-generation sequencing have clarified the correlation between intestinal microbiota and inflammatory bowel disease. Fecal microbiota transplantation (FMT) for patients with ulcerative colitis (UC) is proposed as a potential approach to resolving their dysbiosis; however, its safety and efficacy have not been confirmed. This single-arm, open-label, non-randomized study aimed to evaluate the safety and efficacy of FMT for Japanese patients with UC as the first registered clinical trial in Japan.

METHODS:

We enrolled 10 patients with active UC despite medical therapy. The donors were the patients' relatives and were carefully screened for infectious diseases. Fecal material was administered via colonoscopy, and the primary endpoint was the presence or absence of serious adverse events related to FMT. The secondary endpoint was a change in partial Mayo score at 12 weeks post-FMT. Scores ≤2 were considered a clinical response. Fecal samples were collected to follow changes in gut microbiota, while extracted complementary DNA were analyzed by a next-generation sequencer. We obtained written informed consent from all patients and donors. This study was approved by our Institutional Review Board and is registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN 000012814).

RESULTS:

Five patients with moderate disease and five with severe disease were enrolled. No severe adverse effects were observed. One patient achieved clinical response; however, none of the patients' microbiota diversity recovered to the donor levels.

CONCLUSIONS:

The use of single FMT for UC was safe; however, we failed to show its clinical efficacy and potential to change the intestinal microbiota.

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