Notch signaling pathway: architecture, disease, and therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 24, 2022

Abstract The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that signaling is an evolutionarily conserved pathway. receptors undergo three cleavages and translocate into the nucleus to regulate transcription of target genes. deeply participates in development homeostasis multiple tissues organs, aberration which results cancerous noncancerous diseases. However, recent indicate outcomes are changeable highly dependent on context. In terms cancers, can both promote inhibit tumor various types cancer. overall performance NOTCH-targeted therapies clinical trials has failed meet expectations. Additionally, mutation been proposed as a predictive biomarker for immune checkpoint blockade therapy many cancers. Collectively, pathway needs be integrally assessed with new perspectives inspire discoveries applications. this review, we focus classical latest findings related illustrate history, architecture, regulatory mechanisms, contributions physiological development, diseases, therapeutic applications microenvironment cancer immunotherapy also highlighted. We hope review will help not only beginners but experts systematically thoroughly understand

Language: Английский

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Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota

Cancer Letters, Journal Year: 2019, Volume and Issue: 469, P. 456 - 467

Published: Nov. 14, 2019

Language: Английский

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Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis

Cancer Cell, Journal Year: 2019, Volume and Issue: 36(3), P. 319 - 336.e7

Published: Sept. 1, 2019

The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) Kras

Language: Английский

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Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells

Medical Sciences, Journal Year: 2018, Volume and Issue: 6(2), P. 31 - 31

Published: April 13, 2018

Colon cancer is the third most common worldwide. Most colorectal occurrences are sporadic, not related to genetic predisposition or family history; however, 20-30% of patients with have a history and 5% these tumors arise in setting Mendelian inheritance syndrome. In many patients, development preceded by benign neoplastic lesion: either an adenomatous polyp serrated polyp. Studies carried out last years characterized main molecular alterations occurring cancers, showing that tumor each patient displays from two eight driver mutations. The ensemble studies, including gene expression has led proposed classifications identification four/five non-overlapping groups. homeostasis rapidly renewing intestinal epithelium ensured few stem cells present at level base crypts. Various experimental evidence suggests cancers may derive malignant transformation acquire cell properties following transformation. seem be involved chemoresistance, radioresistance relapse.

Language: Английский

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Mutant p53 in colon cancer

Journal of Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 11(4), P. 267 - 276

Published: Nov. 27, 2018

The accumulation of genetic alterations in driver genes is responsible for the development and malignant progression colorectal cancer. Comprehensive genome analyses have revealed genes, including APC, KRAS, TGFBR2, TP53, whose mutations are frequently found human cancers. Among them, p53 mutation ~60% cancers, a majority missense-type at 'hot spots', suggesting an oncogenic role mutant by 'gain-of-function' mechanisms. Mouse model studies shown that one these mutations, R270H (corresponding to R273H), causes submucosal invasion intestinal tumors, while loss wild-type has limited effect on process. Furthermore, same promotes metastasis when combined with Kras activation TGF-β suppression. Importantly, either or induces NF-κB variety mechanisms, such as increasing promoter accessibility chromatin remodeling, which may contribute epithelial–mesenchymal transition. These results indicate together accelerate late stage cancer through both inflammatory pathways. Accordingly, suppression function via inhibition nuclear expected be effective strategy against

Language: Английский

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Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis

Cancer Research, Journal Year: 2017, Volume and Issue: 77(10), P. 2620 - 2632

Published: April 18, 2017

Abstract Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the contributes to tumor distribution, we generated germ-free (GF) ApcMin/+and ApcMin/+;Il10−/− mice exposed them specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found that colon tumorigenesis significantly correlated with inflammation in SPF-housed ApcMin/+;Il10−/−, but not ApcMin/+mice. In contrast, small neoplasia development age both ApcMin/+ mice. GF conventionalized by an SPF had more tumors compared Gnotobiotic studies revealed while Fusobacterium nucleatum clinical isolates FadA Fap2 adhesins failed induce tumorigenesis, pks+Escherichia coli promoted model a colibactin-dependent manner, suggesting colibactin is driver carcinogenesis. Our results suggest distinct etiology cancers different locations gut, where cancer primarily driven microbiome, driving force for intestine cancer. Cancer Res; 77(10); 2620–32. ©2017 AACR.

Language: Английский

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Organoid models of gastrointestinal cancers in basic and translational research

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2020, Volume and Issue: 17(4), P. 203 - 222

Published: Feb. 25, 2020

Language: Английский

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Mechanisms of metastatic colorectal cancer

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(9), P. 609 - 625

Published: May 28, 2024

Language: Английский

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TCF/LEF Transcription Factors: An Update from the Internet Resources

Cancers, Journal Year: 2016, Volume and Issue: 8(7), P. 70 - 70

Published: July 20, 2016

T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as main downstream effectors of Wnt signaling pathway. The mammalian TCF/LEF comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known TCF1, TCF3, TCF4, respectively). display common structural features are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed gene targeting studies; however, individual members also exhibit unique that not recapitulated by related proteins. In present viewpoint, we summarized our current knowledge about specific TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, phenotypes obtained upon mouse. addition, employed several publicly available databases web tools to evaluate expression production gene-specific isoforms human cells tissues.

Language: Английский

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Neutrophils suppress tumor‐infiltrating T cells in colon cancer via matrix metalloproteinase‐mediated activation of TGF β

EMBO Molecular Medicine, Journal Year: 2019, Volume and Issue: 12(1)

Published: Dec. 2, 2019

Article2 December 2019Open Access Source DataTransparent process Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGFβ Markus Germann Corresponding Author [email protected] orcid.org/0000-0001-8306-6918 Swiss Institute for Experimental Cancer Research (ISREC), School Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Search more papers by this author Nadine Zangger Bioinformatics Core Facility, (SIB), Department Oncology, Translational and Statistics, Center University Marc-Olivier Sauvain Hospital, Visceral Surgery, Christine Sempoux Pathology, Amber D Bowler Pratyaksha Wirapati Lana E Kandalaft Ludwig Research, Mauro Delorenzi Sabine Tejpar Digestive Oncology Unit, Hospital Gasthuisberg, Leuven, Belgium George Coukos Freddy Radtke orcid.org/0000-0003-4315-4045 Information *,1, Zangger1,2,3, Sauvain4,5, Sempoux6, Bowler1, Wirapati2,3, Kandalaft4,7, Delorenzi2,3, Tejpar8, Coukos4,7 *,1 1Swiss 2Bioinformatics 3Department 4Department 5Department 6Institute 7Ludwig 8Digestive *Corresponding author. Tel: +41 79 4631922; E-mail: 21 69330771; EMBO Mol Med (2020)12:e10681https://doi.org/10.15252/emmm.201910681 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract High T-cell infiltration colorectal (CRC) correlates with favorable disease outcome immunotherapy response. This, however, is only observed small subset CRC patients. A better understanding factors influencing tumor could inspire novel therapeutic approaches achieve broader responsiveness. Here, we investigated cell-suppressive properties different myeloid cell types an inducible mouse model. The most potent inhibitors activity were neutrophils. Gene expression analysis combined vitro vivo tests indicated that suppression mediated neutrophil-secreted metalloproteinase latent TGFβ. patient neutrophils similarly suppressed vitro, public gene datasets suggested lowest CRCs neutrophil activation. Thus, interaction TGFβ-rich microenvironment may represent conserved immunosuppressive mechanism CRC. Synopsis Neutrophil characteristic human tumors, initiated during formation early adenomas. contribute immune-suppressive through secretion MMPs, which activate stored stroma. Inflammatory counteracted adenoma at earliest stage, but excluded progression. In contrast, infiltrated early-stage as well established adenomas, where they inflammatory microenvironment. mice, targeting or neutrophil-mediated promoted activity. Similar carcinomas frequently Human high had infiltration. Introduction Inflammation major hallmark (Grivennikov et al, 2010; Hanahan Weinberg, 2011), both pro- anti-tumorigenic have been described. cell-mediated anti-tumor immune response basis (Angell Galon, 2013; Ribas Wolchok, 2018). Many cells, such macrophages, dendritic monocytes, neutrophils, not act antigen presenting promote responses, also many contexts Joyce Fearon, 2015; Kumar 2016). CRC, contexture are heterogeneous reflective its pathology (Guinney Dienstmann Tabernero, 2017; Pages Activated prominent primary tumors characterized microsatellite instability (MSI) (Mlecnik 2016), thereof correlated prognoses (Pages Remarkable success checkpoint blockade (ICB), bolsters immunity, solid (Ribas 2018), led initiation clinical trials ICB Unfortunately, largely unsuccessful effective was MSI cases (Le Overman 2017). vast unresponsiveness patients therapy suggests there be unknown contributing (TME). Immune-promoting signals present normal essential maintain tissue homeostasis (Saleh Trinchieri, 2011). lack variety cancers thought depend on aberrant TME (Llosa Topalian Le Whether these immune-evasive mechanisms induced exclusively develop first lesions currently unknown. benign adenomatous precursor variably (McLean 2011; Maglietta How influences progression Mouse models intestinal recapitulate allow functional investigation implication (Jackstadt Sansom, investigate influence subsets murine We demonstrate thus prevent them from inhibiting formation. Further, identify Finally, found feature concomitant plus indicative tumors. Results depletion enhances distinct used research recent decades majority based loss function Apc similar genetic alterations leading hyperactivation Wnt signaling pathway than 90% (Cancer Genome Atlas, 2012) sufficient induce mice (Shibata 1997). Most studies use Cre recombinase-based predominantly intestine Because humans confined intestine, opted Apcfl/fl-Cdx2CreERT2 induces specifically (Feng 2013). Injecting low dose Tamoxifen Cre-recombinase crypt foci within 3 weeks macroscopic 6–14 weeks. Activation counteracts instable 2017) advanced transplantation (Lau 2017), role adenomas has so far. To test whether affect continuously injected anti-CD4 anti-CD8 neutralizing antibodies after (Fig 1A). This regimen depleted peripheral diminished about 60% 1B Appendix Fig S1A B). Despite incomplete increased total volume result numbers tendency size 1C). Within week initiation, no effect number nuclear cytoplasmic β-catenin staining (Appendix S1C D), suggesting transformation initiating recombinase-mediated knockout (Barker 2009). phenotype S2A Taken together, indicates already counteract accordingly promotes development. inhibition cytotoxic response, initiation. contrast co-depletion CD4+ CD8+ alone burden S2C D). either concert mediate Figure 1. leads growth A. treated and, beginning day following treatment, (αCD4/αCD8, blue dots) IgG control (black twice 6 B. FACS relative TCRβ+ content blood (left panel) (right end treatments (A). αCD4/αCD8: n = 10; IgG: 6. C. Tumor panel), (middle average per assessed resection treatments. 9. Data information: (B–C), statistical performed unpaired two-tailed Student's t-tests. *P < 0.05; ****P 0.0001. Exact P-values provided Table S4. Download figure PowerPoint Low-inflammatory characterize Having discovered wanted persisted For purpose, analyzed distribution tissues healthy immunohistochemistry over time. lower 2A B, S3 A), cell-exclusion general exclusion specifically, compared colon. Infiltration CD45+ between comparable S4B–D), contraindicating (Figs 2C–F EV1A, S4E). inversely monocyte 2G). case neither macrophages EV1B), nor expressing CD206 EV1C), marker specific (Mantovani Investigating subsets, Foxp3+ regulatory (Tregs) decreased 2H–J). fraction potentially Tregs among 2K). interferon-γ (INFγ)+, granzyme B+, interleukin 17A+ EV1D), means reduced EV1E). These data indicate reduction suggest potential involvement monocytes reducing 2. infiltrationImmune mice. Relative (n 10) 22). Anti-CD3 immunostaining representative section derived panel: higher magnification area middle panel). CD11b+ 16) 16). D. Anti-Gr1 E–G. MHCII− Gr1hi (E) Gr1lo (F) 13) (G) Correlation sample-matched tumor-derived H–J. Percentage hematopoietic 11). (H) cells. (I) (J) (Tregs). K. (CD45+ TCRβ+) (A), (C), (E–K), individual determined tissue-derived single suspension using type-specific analysis. Each dot represents pooled one mouse. (E), (F), (H–K), ***P 0.001; Statistical linear regression. available online figure. 2 [emmm201910681-sup-0003-SDataFig2.zip] Click here expand EV1. MHCII+ macrophage 8) 14). CD206+ isolated D, E. IFNγ+, GZMB+, IL17A+ effector displayed percentage (D) (E). (A–E), each (D, left panel); Colon: 7. Tumor: 10. 13. right (E, 11. (D), **P 0.01. (B) proliferation Suppression subtypes various previously described (Talmadge Gabrilovich, 2013), IL10 enzymatic arginase, nitric oxide synthetase (iNOS), adenosine-converting enzymes (CD39 CD73), indoleamine-deoxygenase, cyclooxygenase-2 (PTGS2) (Gabrilovich 2012; Bronte 2016; Shaul Fridlender, One core characteristics their ability inhibit (Bronte determine any subpopulations our model exhibit activity, co-culture experiments vitro-activated Figs S3A S5A–F). lesser extent, inhibited 3A), potential. 3. activated increasing ratios macrophages. index proliferated days condition when cultured alone. lymph nodes wild-type Neutrophils, 4), 3), 4) sample. Bars mean ± SD. setup. Eight treatment animals anti-Gr1 antibody (αGr1, three times/week) CXCR2 inhibitor (CXCR2i, five (three DMSO (five 1–3 αGr1 + CXCR2i 7) Average 9) 12) (B). sections F. extracted G. IFNγ IL17A two-way ANOVA Dunnett's multiple comparison tests. (C–D) (F–G), shown two independent experiments. [emmm201910681-sup-0004-SDataFig3.zip] tumor-bearing reduces activates present. Together fact involved exclusion. hypothesis, stage expected 3B). 3C S6A B) compellingly, resulted consequently, 3D S6C). Tregs, trend 3E–G S6D). analogy EV2). When experimental setting co-depleted, longer EV2. Effect A–C. 1 post-treatment control, (αGr1+CXCR2i; αNe) (αCD4+αCD8+) (αT 5 Colons then excised (A) Ly6Clo SSChi scored (C). (A–C), Ctrl: 17. αNe: αT+αNe: (C) 18. strongly impair such, part sustaining depletion, treating colony-stimulating factor 1-receptor S6E–G). express genes associated how suppression, RNA-sequencing sorted Global highly altered indicating undergo substantial transcriptional upon S7A Clear phenotypic differences circulating counterparts (Kumar Both expressed Arginase 2, CD39 CD73, IL10, iNOS, Ptgs2 levels S7C). all implicated known Lanitis Accordingly, transwell experiment results cell-suppress

Language: Английский

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