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Huang X, Chen W, Wang Y, Shytikov D, Wang Y, Zhu W, Chen R, He Y, Yang Y, Guo W. Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control. Front Med 2025; 19:23-52. [PMID: 39745621 DOI: 10.1007/s11684-024-1107-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 09/18/2024] [Indexed: 02/27/2025]
Abstract
Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
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Affiliation(s)
- Xianzhe Huang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wenwei Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanyan Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Dmytro Shytikov
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanwen Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wangyi Zhu
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Ruyi Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yuwei He
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanjia Yang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wei Guo
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China.
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Biomedical and Health Translational Research Center of Zhejiang Province, Jiaxing, 314400, China.
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Yan Z, Liu Y, Yuan Y. The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer. Cell Death Discov 2024; 10:512. [PMID: 39719478 DOI: 10.1038/s41420-024-02275-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity. In this paper, based on the review of the characteristics of normal differentiation of gastric epithelial cells and their markers, the four main phenotypes of gastric epithelial cell remodeling and their relationship with gastric cancer (GC) are drawn. Furthermore, we summarize the regulatory factors and mechanisms that affect gastric epithelial cell plasticity and outline the current status of research and future prospection for the treatment targeting gastric epithelial cell plasticity. This study has important theoretical reference value for the in-depth exploration of epithelial cell plasticity and the tumor heterogeneity caused by it, as well as for the precise treatment of GC.
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Affiliation(s)
- Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
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3
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Lee SH, Won Y, Gibbs D, Caldwell B, Goldstein A, Choi E, Goldenring JR. Amphiregulin Switches Progenitor Cell Fate for Lineage Commitment During Gastric Mucosal Regeneration. Gastroenterology 2024; 167:469-484. [PMID: 38492892 PMCID: PMC11260537 DOI: 10.1053/j.gastro.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND & AIMS Isthmic progenitors, tissue-specific stem cells in the stomach corpus, maintain mucosal homeostasis by balancing between proliferation and differentiation to gastric epithelial lineages. The progenitor cells rapidly adopt an active state in response to mucosal injury. However, it remains unclear how the isthmic progenitor cell niche is controlled during the regeneration of damaged epithelium. METHODS We recapitulated tissue recovery process after acute mucosal injury in the mouse stomach. Bromodeoxyuridine incorporation was used to trace newly generated cells during the injury and recovery phases. To define the epithelial lineage commitment process during recovery, we performed single-cell RNA-sequencing on epithelial cells from the mouse stomachs. We validated the effects of amphiregulin (AREG) on mucosal recovery, using recombinant AREG treatment or AREG-deficient mice. RESULTS We determined that an epidermal growth factor receptor ligand, AREG, can control progenitor cell lineage commitment. Based on the identification of lineage-committed subpopulations in the corpus epithelium through single-cell RNA-sequencing and bromodeoxyuridine incorporation, we showed that isthmic progenitors mainly transition into short-lived surface cell lineages but are less frequently committed to long-lived parietal cell lineages in homeostasis. However, mucosal regeneration after damage directs the lineage commitment of isthmic progenitors towards parietal cell lineages. During recovery, AREG treatment promoted repopulation with parietal cells, while suppressing surface cell commitment of progenitors. In contrast, transforming growth factor-α did not alter parietal cell regeneration, but did induce expansion of surface cell populations. AREG deficiency impairs parietal cell regeneration but increases surface cell commitment. CONCLUSIONS These data demonstrate that different epidermal growth factor receptor ligands can distinctly regulate isthmic progenitor-driven mucosal regeneration and lineage commitment.
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Affiliation(s)
- Su-Hyung Lee
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
| | - Yoonkyung Won
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David Gibbs
- Institute for Systems Biology, Seattle, Washington
| | - Brianna Caldwell
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anna Goldstein
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Eunyoung Choi
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - James R Goldenring
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee.
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Zhang W, Wang S, Zhang H, Meng Y, Jiao S, An L, Zhou Z. Modeling human gastric cancers in immunocompetent mice. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0124. [PMID: 38940675 PMCID: PMC11271222 DOI: 10.20892/j.issn.2095-3941.2024.0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/14/2024] [Indexed: 06/29/2024] Open
Abstract
Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. GC is determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions of the stomach; and displays high heterogeneity, with different cellular origins and diverse histological and molecular features. This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics. In the past decade, great progress has been made in the study of GC, particularly in molecular subtyping, investigation of the immune microenvironment, and defining the evolutionary path and dynamics. Preclinical mouse models, particularly immunocompetent models that mimic the cellular and molecular features of human GC, in combination with organoid culture and clinical studies, have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion, and the development of novel therapeutic strategies. Herein, we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models, emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.
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Affiliation(s)
- Weihong Zhang
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shilong Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hui Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yan Meng
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liwei An
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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Adkins-Threats M, Arimura S, Huang YZ, Divenko M, To S, Mao H, Zeng Y, Hwang JY, Burclaff JR, Jain S, Mills JC. Metabolic regulator ERRγ governs gastric stem cell differentiation into acid-secreting parietal cells. Cell Stem Cell 2024; 31:886-903.e8. [PMID: 38733994 PMCID: PMC11162331 DOI: 10.1016/j.stem.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 02/26/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024]
Abstract
Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show that they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. EsrrgP2ACreERT2 lineage tracing revealed that Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially express SMAD4 and SP1 transcriptional targets and the GTPases regulating acid-secretion signal transduction. As progenitors matured, ERRγ-dependent metabolic transcripts predominated. Organoid and mouse studies validated the requirement of ERRγ for PC differentiation. Our work chronicles stem cell differentiation along a single lineage in vivo and suggests ERRγ as a therapeutic target for PC-related disorders.
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Affiliation(s)
- Mahliyah Adkins-Threats
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Division of Biomedical and Biological Sciences, Washington University, St. Louis, MO 63130, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Sumimasa Arimura
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yang-Zhe Huang
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Margarita Divenko
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarah To
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Heather Mao
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jenie Y Hwang
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Laboratory Medicine, University of Texas Health San Antonio, San Antonio, TX 78249, USA
| | - Joseph R Burclaff
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA
| | - Shilpa Jain
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason C Mills
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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Li M, He W, Wang F, Zhang P, Zhang X, Li Q, Liu T, Li Y. High expression of NOTCH2 in gastric adenocarcinoma: A novel early diagnostic target. J Gastroenterol Hepatol 2024; 39:1115-1122. [PMID: 38577711 DOI: 10.1111/jgh.16540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 02/16/2024] [Accepted: 02/27/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND AND AIM NOTCH2 is overexpressed in gastric cancer (GC), and its enhanced activity is significantly correlated with worse tumor characteristics. We aim to analyze the clinicopathologic correlation between NOTCH2 and the molecular typing of GC by immunohistochemistry and by transcriptional sequencing. METHODS In this immunohistochemical study, we detected NOTCH2, EBER, P53, HER2, MLH1, MSH2, PMS2, and MSH6 and evaluated the association of NOTCH2 with clinical and histopathological features in a large single-institutional series of gastric adenocarcinomas (n = 488). The correlation was also investigated between immunohistochemical results and survival outcomes. RESULTS High NOTCH2 expression (2+/3+) was found in 139/488 (27.5%) samples analyzed. NOTCH2 expression was correlated with early stage T1 (P < 0.0001), GC in the fundus (P = 0.0364), and positive P53 status (P = 0.0019). We did not find an association between NOTCH2 and HER2, microsatellite instability, EBER, and overall survival. Through RNA sequencing, it was revealed that NOTCH2 plays an important biological function in the pathogenesis and development of GC. CONCLUSIONS Our findings suggested that NOTCH2 may be a potential diagnostic target for GC due to the fact that its high expression is closely associated with the early stages of cancer.
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Affiliation(s)
- Mei Li
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Center of Lanzhou University Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou, China
| | - Wenting He
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
- Center of Lanzhou University Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou, China
| | - Furong Wang
- Department of Pathology, Second Hospital of Lanzhou University, Lanzhou, China
| | - Peng Zhang
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
- Center of Lanzhou University Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou, China
- Department of Pathology, Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaoxia Zhang
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
- Center of Lanzhou University Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou, China
| | - Qinan Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Tao Liu
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
- Center of Lanzhou University Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou, China
| | - Yumin Li
- Second Clinical Medical College of Lanzhou University, Lanzhou, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
- Center of Lanzhou University Digestive System Tumor Translational Medicine Engineering Research Center of Gansu Province, Lanzhou, China
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Mou SI, Sultana T, Chatterjee D, Faruk MO, Hosen MI. Comprehensive characterization of coding and non-coding single nucleotide polymorphisms of the Myoneurin (MYNN) gene using molecular dynamics simulation and docking approaches. PLoS One 2024; 19:e0296361. [PMID: 38165846 PMCID: PMC10760682 DOI: 10.1371/journal.pone.0296361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/11/2023] [Indexed: 01/04/2024] Open
Abstract
Genome-wide association studies (GWAS) identified a coding single nucleotide polymorphism, MYNN rs10936599, at chromosome 3q. MYNN gene encodes myoneurin protein, which has been associated with several cancer pathogenesis and disease development processes. However, there needed to be a more detailed characterization of this polymorphism's (and other coding and non-coding polymorphisms) structural, functional, and molecular impact. The current study addressed this gap and analyzed different properties of rs10936599 and non-coding SNPs of MYNN via a thorough computational method. The variant, rs10936599, was predicted functionally deleterious by nine functionality prediction approaches, like SIFT, PolyPhen-2, and REVEL, etc. Following that, structural modifications were estimated through the HOPE server and Mutation3D. Moreover, the mutation was found in a conserved and active residue, according to ConSurf and CPORT. Further, the secondary structures were predicted, followed by tertiary structures, and there was a significant deviation between the native and variant models. Similarly, molecular simulation also showed considerable differences in the dynamic pattern of the wildtype and mutant structures. Molecular docking revealed that the variant binds with better docking scores with ligand NOTCH2. In addition to that, non-coding SNPs located at the MYNN locus were retrieved from the ENSEMBL database. These were found to disrupt the transcription factor binding regulatory regions; nonetheless, only two affect miRNA target sites. Again, eight non-coding variants were detected in the testes with normalized expression, whereas HaploReg v4.1 unveiled annotations for non-coding variants. In summary, in silico comprehensive characterization of coding and non-coding single nucleotide polymorphisms of MYNN gene will assist researchers to work on MYNN gene and establish their association with certain types of cancers.
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Affiliation(s)
- Sadia Islam Mou
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Tamanna Sultana
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Dipankor Chatterjee
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Md. Omar Faruk
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Md. Ismail Hosen
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
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Loe AKH, Rao-Bhatia A, Wei Z, Kim JE, Guan B, Qin Y, Hong M, Kwak HS, Liu X, Zhang L, Wrana JL, Guo H, Kim TH. YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration. Cell Rep 2023; 42:113497. [PMID: 38041813 DOI: 10.1016/j.celrep.2023.113497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/25/2023] [Accepted: 11/09/2023] [Indexed: 12/04/2023] Open
Abstract
Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.
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Affiliation(s)
- Adrian K H Loe
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Abilasha Rao-Bhatia
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Zhao Wei
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China
| | - Jung-Eun Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Bingxin Guan
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China
| | - Yan Qin
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Minji Hong
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Hyo Sang Kwak
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Xiaoyu Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China
| | - Leyi Zhang
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jeffrey L Wrana
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Haiyang Guo
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China.
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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9
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Krzysiek-Maczka G, Brzozowski T, Ptak-Belowska A. Helicobacter pylori-activated fibroblasts as a silent partner in gastric cancer development. Cancer Metastasis Rev 2023; 42:1219-1256. [PMID: 37460910 PMCID: PMC10713772 DOI: 10.1007/s10555-023-10122-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/20/2023] [Indexed: 12/18/2023]
Abstract
The discovery of Helicobacter pylori (Hp) infection of gastric mucosa leading to active chronic gastritis, gastroduodenal ulcers, and MALT lymphoma laid the groundwork for understanding of the general relationship between chronic infection, inflammation, and cancer. Nevertheless, this sequence of events is still far from full understanding with new players and mediators being constantly identified. Originally, the Hp virulence factors affecting mainly gastric epithelium were proposed to contribute considerably to gastric inflammation, ulceration, and cancer. Furthermore, it has been shown that Hp possesses the ability to penetrate the mucus layer and directly interact with stroma components including fibroblasts and myofibroblasts. These cells, which are the source of biophysical and biochemical signals providing the proper balance between cell proliferation and differentiation within gastric epithelial stem cell compartment, when exposed to Hp, can convert into cancer-associated fibroblast (CAF) phenotype. The crosstalk between fibroblasts and myofibroblasts with gastric epithelial cells including stem/progenitor cell niche involves several pathways mediated by non-coding RNAs, Wnt, BMP, TGF-β, and Notch signaling ligands. The current review concentrates on the consequences of Hp-induced increase in gastric fibroblast and myofibroblast number, and their activation towards CAFs with the emphasis to the altered communication between mesenchymal and epithelial cell compartment, which may lead to inflammation, epithelial stem cell overproliferation, disturbed differentiation, and gradual gastric cancer development. Thus, Hp-activated fibroblasts may constitute the target for anti-cancer treatment and, importantly, for the pharmacotherapies diminishing their activation particularly at the early stages of Hp infection.
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Affiliation(s)
- Gracjana Krzysiek-Maczka
- Department of Physiology, the Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Kraków, Poland.
| | - Tomasz Brzozowski
- Department of Physiology, the Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Kraków, Poland.
| | - Agata Ptak-Belowska
- Department of Physiology, the Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Kraków, Poland
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10
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Hibdon ES, Keeley TM, Merchant JL, Samuelson LC. The bHLH transcription factor ASCL1 promotes differentiation of endocrine cells in the stomach and is regulated by Notch signaling. Am J Physiol Gastrointest Liver Physiol 2023; 325:G458-G470. [PMID: 37698169 PMCID: PMC10887855 DOI: 10.1152/ajpgi.00043.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 09/13/2023]
Abstract
Notch signaling regulates gastrointestinal stem cell proliferation and differentiation yet Notch-regulated transcriptional effectors of gastric epithelial cell differentiation are poorly understood. Here we tested the role of the bHLH transcription factor Achaete-Scute homolog 1 (ASCL1) in gastric epithelial cell differentiation, and its regulation by Notch. Newborn Ascl1 null mice showed a loss of expression of markers of neurogenin-3-dependent enteroendocrine cells, with normal expression of enterochromaffin-like cells, mucous cells, chief cells, and parietal cells. In adult mice, Ascl1 gene expression was observed in the stomach, but not the intestine, with higher expression in antral than corpus epithelium. Lineage tracing in Ascl1-CreERT2; Rosa26-LSL-tdTomato mice revealed single, scattered ASCL1+ cells in the gastric epithelium, demonstrating expression in antral gastrin- and serotonin-producing endocrine cells. ASCL1-expressing endocrine cells persisted for several weeks posttamoxifen labeling with a half-life of approximately 2 months. Lineage tracing in Gastrin-CreERT2 mice demonstrated a similar lifespan for gastrin-producing cells, confirming that gastric endocrine cells are long-lived. Finally, treatment of Ascl1-CreERT2; Rosa26-LSL-tdTomato mice with the pan-Notch inhibitor dibenzazepine increased the number of lineage-labeled cells in the gastric antrum, suggesting that Notch signaling normally inhibits Ascl1 expression. Notch regulation of Ascl1 was also demonstrated in a genetic mouse model of Notch activation, as well as Notch-manipulated antral organoid cultures, thus suggesting that ASCL1 is a key downstream Notch pathway effector promoting endocrine cell differentiation in the gastric epithelium.NEW & NOTEWORTHY Although Notch signaling is known to regulate cellular differentiation in the stomach, downstream effectors are poorly described. Here we demonstrate that the bHLH transcription factor ASCL1 is expressed in endocrine cells in the stomach and is required for formation of neurogenin-3-dependent enteroendocrine cells but not enterochromaffin-like cells. We also demonstrate that Ascl1 expression is inhibited by Notch signaling, suggesting that ASCL1 is a Notch-regulated transcriptional effector directing enteroendocrine cell fate in the mouse stomach.
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Affiliation(s)
- Elise S Hibdon
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
| | - Theresa M Keeley
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
| | - Juanita L Merchant
- Department of Medicine, University of Arizona, Tucson, Arizona, United States
| | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
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11
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He Y, He P, Lu S, Dong W. KIFC3 Regulates the progression and metastasis of gastric cancer via Notch1 pathway. Dig Liver Dis 2023; 55:1270-1279. [PMID: 36890049 DOI: 10.1016/j.dld.2023.02.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/19/2023] [Accepted: 02/14/2023] [Indexed: 03/10/2023]
Abstract
INTRODUCTION KIFC3 is a member of the kinesin family which has shown great promise in cancer therapy recently. In this study, we sought to elucidate the role of KIFC3 in the development of GC and its possible mechanisms. METHODS Two databases and a tissue microarray were used to explore the expression of KIFC3 and its correlation with patients' clinicopathological characteristics. Cell proliferation was examined by cell counting kit-8 assay and colony formation assay. Wound healing assay and transwell assay were performed to examine cell metastasis ability. EMT and Notch signaling related proteins were detected by western blot. Additionally, a xenograft tumor model was established to investigate the function of KIFC3 in vivo. RESULTS The expression of KIFC3 was upregulated in GC, and was associated with higher T stage and poor prognosis in GC patients. The proliferation and metastasis ability of GC cells were promoted by KIFC3 overexpression while inhibited by KIFC3 knockdown in vitro and in vivo. Furthermore, KIFC3 might activate the Notch1 pathway to facilitate the progression of GC, and DAPT, an inhibitor of Notch signaling, could reverse this effect. CONCLUSION Together, our data revealed that KIFC3 could enhance the progression and metastasis of GC by activating the Notch1 pathway.
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Affiliation(s)
- Yang He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China
| | - Pengzhan He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China
| | - Shimin Lu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory of Renmin Hospital, Wuhan, Hubei Province, China.
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12
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Liu M, Liu Q, Zou Q, Li J, Chu Z, Xiang J, Chen WQ, Miao ZF, Wang B. The composition and roles of gastric stem cells in epithelial homeostasis, regeneration, and tumorigenesis. Cell Oncol (Dordr) 2023; 46:867-883. [PMID: 37010700 DOI: 10.1007/s13402-023-00802-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2023] [Indexed: 04/04/2023] Open
Abstract
The epithelial lining of the stomach undergoes rapid turnover to preserve its structural and functional integrity, a process driven by long-lived stem cells residing in the antral and corpus glands. Several subpopulations of gastric stem cells have been identified and their phenotypic and functional diversities linked to spatiotemporal specification of stem cells niches. Here, we review the biological features of gastric stem cells at various locations of the stomach under homeostatic conditions, as demonstrated by reporter mice, lineage tracing, and single cell sequencing. We also review the role of gastric stem cells in epithelial regeneration in response to injury. Moreover, we discuss emerging evidence demonstrating that accumulation of oncogenic drivers or alteration of stemness signaling pathways in gastric stem cells promotes gastric cancer. Given a fundamental role of the microenvironment, this review highlights the role reprogramming of niche components and signaling pathways under pathological conditions in dictating stem cell fate. Several outstanding issues are raised, such as the relevance of stem cell heterogeneity and plasticity, and epigenetic regulatory mechanisms, to Helicobacter pylori infection-initiated metaplasia-carcinogenesis cascades. With the development of spatiotemporal genomics, transcriptomics, and proteomics, as well as multiplexed screening and tracing approaches, we anticipate that more precise definition and characterization of gastric stem cells, and the crosstalk with their niche will be delineated in the near future. Rational exploitation and proper translation of these findings may bring forward novel modalities for epithelial rejuvenation and cancer therapeutics.
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Affiliation(s)
- Meng Liu
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, P. R. China
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Qin Liu
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Qiang Zou
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, P. R. China
| | - Jinyang Li
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Zhaole Chu
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Junyu Xiang
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Wei-Qing Chen
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, P. R. China.
| | - Zhi-Feng Miao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, 110001, P. R. China.
| | - Bin Wang
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China.
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, P. R. China.
- Jinfeng Laboratory, Chongqing, 401329, P. R. China.
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13
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Takada H, Sasagawa Y, Yoshimura M, Tanaka K, Iwayama Y, Hayashi T, Isomura-Matoba A, Nikaido I, Kurisaki A. Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis. Nat Commun 2023; 14:3750. [PMID: 37386010 PMCID: PMC10310803 DOI: 10.1038/s41467-023-39113-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/30/2023] [Indexed: 07/01/2023] Open
Abstract
Defects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.
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Affiliation(s)
- Hitomi Takada
- Laboratory of Stem Cell Technologies, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Nara, Japan
| | - Yohei Sasagawa
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
| | - Mika Yoshimura
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Kaori Tanaka
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Yoshimi Iwayama
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
| | - Tetsutaro Hayashi
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Ayako Isomura-Matoba
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Itoshi Nikaido
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan.
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
- Master's/Doctoral Program in Life Science Innovation (Bioinformatics), Degree Programs in Systems and Information Engineering, Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Akira Kurisaki
- Laboratory of Stem Cell Technologies, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Nara, Japan.
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14
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Zhong C, Wu C, Lin Y, Lin D. Refined expression quantitative trait locus analysis on adenocarcinoma at the gastroesophageal junction reveals susceptibility and prognostic markers. Front Genet 2023; 14:1180500. [PMID: 37265963 PMCID: PMC10230079 DOI: 10.3389/fgene.2023.1180500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/03/2023] [Indexed: 06/03/2023] Open
Abstract
Objectives: This study aimed to explore cell type level expression quantitative trait loci (eQTL) in adenocarcinoma at the gastroesophageal junction (ACGEJ) and identify susceptibility and prognosis markers. Methods: Whole-genome sequencing (WGS) was performed on 120 paired samples from Chinese ACGEJ patients. Germline mutations were detected by GATK tools. RNA sequencing (RNA-seq) data on ACGEJ samples were taken from our previous studies. Public single-cell RNA sequencing (scRNA-seq) data were used to produce the proportion of epithelial cells. Matrix eQTL and a linear mixed model were used to identify condition-specific cis-eQTLs. The R package coloc was used to perform co-localization analysis with the public data of genome-wide association studies (GWASs). Log-rank and Cox regression tests were used to identify survival-associated eQTL and genes. Functions of candidate risk loci were explored by experimental validation. Results: Refined eQTL analyses of paired ACGEJ samples were performed and 2,036 potential ACGEJ-specific eQTLs with East Asian specificity were identified in total. ACGEJ-gain eQTLs were enriched at promoter regions more than ACGEJ-loss eQTLs. rs658524 was identified as the top eQTL close to the transcription start site of its paired gene (CTSW). rs2240191-RASAL1, rs4236599-FOXP2, rs4947311-PSORS1C1, rs13134812-LOC391674, and rs17508585-CDK13-DT were identified as ACGEJ-specific susceptibility eQTLs. rs309483-LINC01355 was associated with the overall survival of ACGEJ patients. We explored functions of candidate eQTLs such as rs658524, rs309483, rs2240191, and rs4947311 by experimental validation. Conclusion: This study provides new risk loci for ACGEJ susceptibility and effective disease prognosis biomarkers.
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Affiliation(s)
- Ce Zhong
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Lin
- Beijing Advanced Innovation Center for Genomics (ICG), Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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15
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Huebner AJ, Gorelov RA, Deviatiiarov R, Demharter S, Kull T, Walsh RM, Taylor MS, Steiger S, Mullen JT, Kharchenko PV, Hochedlinger K. Dissection of gastric homeostasis in vivo facilitates permanent capture of isthmus-like stem cells in vitro. Nat Cell Biol 2023; 25:390-403. [PMID: 36717627 DOI: 10.1038/s41556-022-01079-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 12/12/2022] [Indexed: 02/01/2023]
Abstract
The glandular stomach is composed of two regenerative compartments termed corpus and antrum, and our understanding of the transcriptional networks that maintain these tissues is incomplete. Here we show that cell types with equivalent functional roles in the corpus and antrum share similar transcriptional states including the poorly characterized stem cells of the isthmus region. To further study the isthmus, we developed a monolayer two-dimensional (2D) culture system that is continually maintained by Wnt-responsive isthmus-like cells capable of differentiating into several gastric cell types. Importantly, 2D cultures can be converted into conventional three-dimensional organoids, modelling the plasticity of gastric epithelial cells in vivo. Finally, we utilized the 2D culture system to show that Sox2 is both necessary and sufficient to generate enterochromaffin cells. Together, our data provide important insights into gastric homeostasis, establish a tractable culture system to capture isthmus cells and uncover a role for Sox2 in enterochromaffin cells.
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Affiliation(s)
- Aaron J Huebner
- Massachusetts General Hospital Department of Molecular Biology, Boston, MA, USA
- Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Rebecca A Gorelov
- Massachusetts General Hospital Department of Molecular Biology, Boston, MA, USA
- Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Ruslan Deviatiiarov
- Institute of Fundamental Medicine and Biology, Kazan Feberal University, Kazan, Russia
| | - Samuel Demharter
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Tobias Kull
- Massachusetts General Hospital Department of Molecular Biology, Boston, MA, USA
- Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Ryan M Walsh
- Massachusetts General Hospital Department of Molecular Biology, Boston, MA, USA
- Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Marty S Taylor
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Simon Steiger
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - John T Mullen
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Peter V Kharchenko
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- San Diego Institute, Altos Labs, San Diego, CA, USA.
| | - Konrad Hochedlinger
- Massachusetts General Hospital Department of Molecular Biology, Boston, MA, USA.
- Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA, USA.
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
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16
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Yao Y, Wei L, Chen Z, Li H, Qi J, Wu Q, Zhou X, Lu Y, Zhu X. Single-cell RNA sequencing: Inhibited Notch2 signalling underlying the increased lens fibre cells differentiation in high myopia. Cell Prolif 2023:e13412. [PMID: 36717696 PMCID: PMC10392066 DOI: 10.1111/cpr.13412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/26/2022] [Accepted: 01/18/2023] [Indexed: 02/01/2023] Open
Abstract
High myopia is the leading cause of blindness worldwide. It promotes the overgrowth of lens, which is an important component of ocular refractive system, and increases the risks of lens surgery. While postnatal growth of lens is based on the addition of lens fibre cells (LFCs) supplemented by proliferation and differentiation of lens epithelial cells (LECs), it remains unknown how these cellular processes change in highly myopic eyes and what signalling pathways may be involved. Single-cell RNA sequencing was performed and a total of 50,375 single cells isolated from the lens epithelium of mouse highly myopic and control eyes were analysed to uncover their underlying transcriptome atlas. The proportion of LFCs was significantly higher in highly myopic eyes. Meanwhile, Notch2 signalling was inhibited during lineage differentiation trajectory towards LFCs, while Notch2 predominant LEC cluster was significantly reduced in highly myopic eyes. In consistence, Notch2 was the top down-regulated gene identified in highly myopic lens epithelium. Further validation experiments confirmed NOTCH2 downregulation in the lens epithelium of human and mouse highly myopic eyes. In addition, NOTCH2 knockdown in primary human and mouse LECs resulted in enhanced differentiation towards LFCs accompanied by up-regulation of MAF and CDKN1C. These findings indicated an essential role of NOTCH2 inhibition in lens overgrowth of highly myopic eyes, suggesting a therapeutic target for future interventions.
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Affiliation(s)
- Yunqian Yao
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Ling Wei
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Zhenhua Chen
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Hao Li
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Jiao Qi
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Qingfeng Wu
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Beijing, China.,Chinese Institute for Brain Research, Beijing, China.,Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xingtao Zhou
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Yi Lu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.,State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Xiangjia Zhu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,National Health Center Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.,State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
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17
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Chai H, Pan C, Zhang M, Huo H, Shan H, Wu J. Histone methyltransferase SETD1A interacts with notch and promotes notch transactivation to augment ovarian cancer development. BMC Cancer 2023; 23:96. [PMID: 36707804 PMCID: PMC9883963 DOI: 10.1186/s12885-023-10573-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 12/27/2022] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND High expression of SETD1A, a histone methyltransferase that specifically methylates H3K4, acted as a key oncogene in several human cancers. However, the function and underlying molecular mechanism of SETD1A in ovarian cancer (OV) remain markedly unknown. METHODS The expression of SETD1A in OV were detected by Western blot and analyzed online, and the prognosis of STED1A in OV were analyzed online. The protein and mRNA levels were determined by Western blot and RT-qPCR. The cell proliferatin, migration and invasion were measured by CCK-8 and transwell assays. The protein interaction was detected by co-IP assay. The interaction between protein and DNA was performed by ChIP assay. The tumor growth in vivo was performed by xenograft tumor model. RESULTS SETD1A was overexpressed in OV and a predictor of poor prognosis. Overexpression of SETD1A augmented the abilities of cell proliferation, migration, and invasion in MRG1 and OVCAR5 cells. In comparison, SETD1A knockdown suppressed cell growth, migration, and invasion in SKOV3 and Caov3 cells. Specifically, SETD1A enhanced Notch signaling by promoting the expression of Notch target genes, such as Hes1, Hey1, Hey2, and Heyl. Mechanistically, SETD1A interacted with Notch1 and methylated H3K4me3 at Notch1 targets to enhance Notch signaling. In addition, restoration of Notch1 in SETD1A-knockdown OV cells recovered cell proliferation, migration and invasion, which was inhibited by SETD1A knockdown. Furthermore, reduction of SETD1A suppressed tumorigenesis in vivo. CONCLUSION In conclusion, our results highlighted the key role of SETD1A in OV development and proved that SETD1A promotes OV development by enhancing Notch1 signaling, indicating that SETD1A may be a novel target for OV treatment.
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Affiliation(s)
- Hongjuan Chai
- grid.412523.30000 0004 0386 9086Department of Gynecology and Obstetrics, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Chunpeng Pan
- grid.412523.30000 0004 0386 9086Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Mingyang Zhang
- grid.263761.70000 0001 0198 0694Department of Forensic Sciences, Soochow University, Suzhou, China
| | - Haizhong Huo
- grid.412523.30000 0004 0386 9086Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Haiyan Shan
- grid.89957.3a0000 0000 9255 8984Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242, Guangji Road, 215000 Suzhou, China
| | - Jugang Wu
- grid.412523.30000 0004 0386 9086Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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18
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Lindholm-Perry AK, Meyer AM, Kern-Lunbery RJ, Cunningham-Hollinger HC, Funk TH, Keel BN. Genes Involved in Feed Efficiency Identified in a Meta-Analysis of Rumen Tissue from Two Populations of Beef Steers. Animals (Basel) 2022; 12:1514. [PMID: 35739852 PMCID: PMC9219435 DOI: 10.3390/ani12121514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
In cattle, the rumen is an important site for the absorption of feed by-products released by bacterial fermentation, and variation in ruminal function plays a role in cattle feed efficiency. Studies evaluating gene expression in the rumen tissue have been performed prior to this. However, validating the expression of genes identified in additional cattle populations has been challenging. The purpose of this study was to perform a meta-analysis of the ruminal transcriptome of two unrelated populations of animals to identify genes that are involved in feed efficiency across populations. RNA-seq data from animals with high and low residual feed intake (RFI) from a United States population of cattle (eight high and eight low RFI) and a Canadian population of cattle (nine high and nine low RFI) were analyzed for differences in gene expression. A total of 83 differentially expressed genes were identified. Some of these genes have been previously identified in other feed efficiency studies. These genes included ATP6AP1, BAG6, RHOG, and YPEL3. Differentially expressed genes involved in the Notch signaling pathway and in protein turnover were also identified. This study, combining two unrelated populations of cattle in a meta-analysis, produced several candidate genes for feed efficiency that may be more robust indicators of feed efficiency than those identified from single populations of animals.
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Affiliation(s)
| | - Allison M. Meyer
- Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA;
| | | | | | - Taran H. Funk
- Meat Animal Research Center, USDA, ARS, U.S. Clay Center, NE 68933, USA; (T.H.F.); (B.N.K.)
| | - Brittney N. Keel
- Meat Animal Research Center, USDA, ARS, U.S. Clay Center, NE 68933, USA; (T.H.F.); (B.N.K.)
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19
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Hoffmann W. Self-Renewal and Cancers of the Gastric Epithelium: An Update and the Role of the Lectin TFF1 as an Antral Tumor Suppressor. Int J Mol Sci 2022; 23:ijms23105377. [PMID: 35628183 PMCID: PMC9141172 DOI: 10.3390/ijms23105377] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022] Open
Abstract
In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5+ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells.
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Affiliation(s)
- Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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20
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Liu H, Du J, Chao S, Li S, Cai H, Zhang H, Chen G, Liu P, Bu P. Fusobacterium nucleatum Promotes Colorectal Cancer Cell to Acquire Stem Cell-Like Features by Manipulating Lipid Droplet-Mediated Numb Degradation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2105222. [PMID: 35170250 PMCID: PMC9035998 DOI: 10.1002/advs.202105222] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/19/2021] [Indexed: 05/26/2023]
Abstract
Fusobacterium nucleatum is a critical microbe that contributes to colorectal cancer progression and chemoresistance. However, whether and how F. nucleatum regulates colorectal cancer stem-like cells (CCSCs) remains unknown. Here, the authors show that F. nucleatum promotes CCSC self-renewal, and non-CCSCs to acquire CCSC features by manipulating cellular lipid accumulation. F. nucleatum infection decreases lipid accumulation in CCSCs by enhancing fatty acid oxidation, thus promoting CCSC self-renewal. In contrast, F. nucleatum increases lipid accumulation in non-CCSCs by promoting fatty acid formation. Lipids are deposited as lipid droplets, which recruits Numb, a key cell fate regulator, through the AP2A/ACSL3 complex, and MDM2, an E3 ubiquitin ligase, though VCP and UBXD8. On lipid droplets, Numb is degraded by MDM2, activating Notch signaling, thus promoting gain of stem-like cell features. Their findings demonstrate that F. nucleatum directly manipulates colorectal cancer cell fate and reveal the mechanism of lipid droplet-mediated Numb degradation for activating Notch signaling.
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Affiliation(s)
- Haiyang Liu
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Junfeng Du
- Department of General Surgerythe 7th Medical CenterChinese PLA General HospitalBeijing100700China
- The 2nd School of Clinical MedicineSouthern Medical UniversityGuangdong510515China
- Medical Department of General Surgerythe 1st Medical CenterChinese PLA General HospitalBeijing100853China
| | - Shanshan Chao
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijing100049China
| | - Shuoguo Li
- Center for Biological ImagingInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Huiyun Cai
- Department of General Surgerythe 7th Medical CenterChinese PLA General HospitalBeijing100700China
| | - Hongjie Zhang
- The core facilityInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Gang Chen
- Department of General Surgerythe 7th Medical CenterChinese PLA General HospitalBeijing100700China
- Medical Department of General Surgerythe 1st Medical CenterChinese PLA General HospitalBeijing100853China
| | - Pingsheng Liu
- National Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- Center for Excellence in BiomacromoleculesChinese Academy of SciencesBeijing100101China
| | - Pengcheng Bu
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of SciencesBeijing100049China
- Center for Excellence in BiomacromoleculesChinese Academy of SciencesBeijing100101China
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21
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Morphogen Signals Shaping the Gastric Glands in Health and Disease. Int J Mol Sci 2022; 23:ijms23073632. [PMID: 35408991 PMCID: PMC8998987 DOI: 10.3390/ijms23073632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/17/2022] Open
Abstract
The adult gastric mucosa is characterised by deep invaginations of the epithelium called glands. These tissue architectural elements are maintained with the contribution of morphogen signals. Morphogens are expressed in specific areas of the tissue, and their diffusion generates gradients in the microenvironment. Cells at different positions in the gland sense a specific combination of signals that instruct them to differentiate, proliferate, regenerate, or migrate. Differentiated cells perform specific functions involved in digestion, such as the production of protective mucus and the secretion of digestive enzymes or gastric acid. Biopsies from gastric precancerous conditions usually display tissue aberrations and change the shape of the glands. Alteration of the morphogen signalling microenvironment is likely to underlie those conditions. Furthermore, genes involved in morphogen signalling pathways are found to be frequently mutated in gastric cancer. We summarise the most recent findings regarding alterations of morphogen signalling during gastric carcinogenesis, and we highlight the new stem cell technologies that are improving our understanding of the regulation of human tissue shape.
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22
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 493] [Impact Index Per Article: 164.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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23
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Goldenring JR, Mills JC. Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond. Gastroenterology 2022; 162:415-430. [PMID: 34728185 PMCID: PMC8792220 DOI: 10.1053/j.gastro.2021.10.036] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 10/21/2021] [Accepted: 10/24/2021] [Indexed: 02/03/2023]
Abstract
The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.
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Affiliation(s)
- James R Goldenring
- Nashville Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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24
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Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research. Cells 2022; 11:cells11020184. [PMID: 35053302 PMCID: PMC8773924 DOI: 10.3390/cells11020184] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/30/2021] [Accepted: 01/02/2022] [Indexed: 12/13/2022] Open
Abstract
There is considerable cellular diversity in the human stomach, which has helped to clarify cell plasticity in normal development and tumorigenesis. Thus, the stomach is an interesting model for understanding cellular plasticity and for developing prospective anticancer therapeutic agents. However, many questions remain regarding the development of cancers in vivo and in vitro in two- or three-dimensional (2D/3D) cultures, as well as the role of Helicobacter pylori (H. p.) infection. Here, we focus on the characteristics of cancer stem cells and their derived 3D organoids in culture, including the formation of stem cell niches. We define the conditions required for such organoid culture in vitro and examine the ability of such models for testing the use of anticancer agents. We also summarize the signaling cascades and the specific markers of stomach-cancer-derived organoids induced by H. p. infection, and their stem cell niches.
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25
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A Comprehensive Bioinformatic Analysis of NOTCH Pathway Involvement in Stomach Adenocarcinoma. DISEASE MARKERS 2021; 2021:4739868. [PMID: 34925644 PMCID: PMC8674080 DOI: 10.1155/2021/4739868] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 11/12/2021] [Indexed: 01/02/2023]
Abstract
Background Activation of NOTCH signaling pathways, which are key regulators of multiple cellular functions, has been frequently implicated in cancer pathogenesis, and NOTCH inhibitors have received much recent focus in the context of cancer therapeutics. However, the role and possible involvement of NOTCH pathways in stomach adenocarcinoma (STAD) are unclear. Here, putative regulatory mechanisms and functions of NOTCH pathways in STAD were investigated. Methods Publicly available data from the TCGA-STAD database were utilized to explore the involvement of canonical NOTCH pathways in STAD by analyzing RNA expression levels of NOTCH receptors, ligands, and downstream genes. Statistical analysis of the data pertaining to cancer and noncancerous samples was performed using R software packages and public databases/webservers. Results Significant differential gene expression between control and STAD samples was noted for all NOTCH receptors (NOTCH1, 2, 3, and 4), the delta-like NOTCH ligands (DLL-3 and 4), and typical downstream genes (HES1 and HEY1). Four genes (NOTCH1, NOTCH2, NOTCH3, and HEY1) presented prognostic values for the STAD outcome in terms of overall survival. Functional enrichment analysis indicated that NOTCH family genes-strongly correlated genes were mainly enriched in several KEGG signaling pathways such as the PI3K-Akt signaling pathway, human papillomavirus infection, focal adhesion, Rap1 signaling pathway, and ECM-receptor interaction. Gene set enrichment analysis (GSEA) results showed that NOTCH family genes-significantly correlated genes were mainly enriched in four signaling pathways, ECM (extracellular matrix), tumor angiogenesis, inflammatory response, and immune regulation. Conclusions NOTCH family genes may play an essential role in the progression of STAD by modulating immune cells and mediating ECM synthesis, angiogenesis, focal adhesion, and PI3K-Akt signaling. Multiple NOTCH family genes are valuable candidate biomarkers or therapeutic targets for the management of STAD.
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26
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Jung HJ, Coleman R, Woodward OM, Welling PA. Doxycycline Changes the Transcriptome Profile of mIMCD3 Renal Epithelial Cells. Front Physiol 2021; 12:771691. [PMID: 34803745 PMCID: PMC8602682 DOI: 10.3389/fphys.2021.771691] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Tetracycline-inducible gene expression systems have been used successfully to study gene function in vivo and in vitro renal epithelial models but the effects of the common inducing agent, doxycycline (DOX), on gene expression are not well appreciated. Here, we evaluated the DOX effects on the transcriptome of a widely used renal epithelial cell model, mIMCD3 cells, to establish a reference. Cells were grown on permeable filter supports in the absence and presence of DOX (3 or 6 days), and genome-wide transcriptome profiles were assessed using RNA-Seq. We found DOX significantly altered the transcriptome profile, changing the abundance of 1,549 transcripts at 3 days and 2,643 transcripts at 6 days. Within 3 days of treatment, DOX significantly decreased the expression of multiple signaling pathways (ERK, cAMP, and Notch) that are associated with cell proliferation and differentiation. Genes associated with cell cycle progression were subsequently downregulated in cells treated with DOX for 6 days, as were genes involved in cellular immune response processes and several cytokines and chemokines, correlating with a remarkable repression of genes encoding cell proliferation markers. The results provide new insight into responses of renal epithelial cells to DOX and a establish a resource for DOX-mediated gene expression systems.
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Affiliation(s)
- Hyun Jun Jung
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Richard Coleman
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Owen M Woodward
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Paul A Welling
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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27
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Horita N, Keeley TM, Hibdon ES, Delgado E, Lafkas D, Siebel CW, Samuelson LC. Delta-like 1-Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in Mouse. Cell Mol Gastroenterol Hepatol 2021; 13:275-287. [PMID: 34438113 PMCID: PMC8599166 DOI: 10.1016/j.jcmgh.2021.08.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Notch pathway signaling maintains gastric epithelial cell homeostasis by regulating stem cell proliferation and differentiation. We previously identified NOTCH1 and NOTCH2 as the key Notch receptors controlling gastric stem cell function. Here, we identify the niche cells and critical Notch ligand responsible for regulating stem cell proliferation in the distal mouse stomach. METHODS Expression of Notch ligands in the gastric antrum was determined by quantitative reverse-transcriptase polymerase chain reaction and cellular localization was determined by in situ hybridization and immunostaining. The contribution of specific Notch ligands to regulate epithelial cell proliferation in adult mice was determined by inducible gene deletion, or by pharmacologic inhibition using antibodies directed against specific Notch ligands. Mouse gastric organoid cultures were used to confirm that Notch ligand signaling was epithelial specific. RESULTS Delta-like 1 (DLL1) and Jagged 1 (JAG1) were the most abundantly expressed Notch ligands in the adult mouse stomach, with DLL1 restricted to the antral gland base and JAG1 localized to the upper gland region. Inhibition of DLL1 alone or in combination with other Notch ligands significantly reduced epithelial cell proliferation and the growth of gastric antral organoids, while inhibition of the other Notch ligands, DLL4, JAG1, and JAG2, did not affect proliferation or organoid growth. Similarly, DLL1, and not DLL4, regulated proliferation of LGR5+ antral stem cells, which express the NOTCH1 receptor. CONCLUSIONS DLL1 is the key Notch ligand regulating epithelial cell proliferation in the gastric antrum. We propose that DLL1-expressing cells at the gland base are Notch niche cells that signal to adjacent LGR5+ antral stem cells to regulate stem cell proliferation and epithelial homeostasis.
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Affiliation(s)
- Nobukatsu Horita
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Theresa M Keeley
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Elise S Hibdon
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Elizabeth Delgado
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Daniel Lafkas
- Department of Discovery Oncology, Genentech, San Francisco, California
| | | | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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28
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Loe AKH, Francis R, Seo J, Du L, Wang Y, Kim JE, Hakim SW, Kim JE, He HH, Guo H, Kim TH. Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy. J Exp Med 2021; 218:211950. [PMID: 33822841 PMCID: PMC8034383 DOI: 10.1084/jem.20200219] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 01/20/2021] [Accepted: 03/05/2021] [Indexed: 12/25/2022] Open
Abstract
Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.
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Affiliation(s)
- Adrian Kwan Ho Loe
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Roshane Francis
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Jieun Seo
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, China.,Tumor Marker Detection Engineering Laboratory of Shandong Province, Jinan, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, China.,Tumor Marker Detection Engineering Laboratory of Shandong Province, Jinan, Shandong, China
| | - Ji-Eun Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Shaheed W Hakim
- St. Joseph's Health Centre, Unity Health Toronto, Toronto, Ontario, Canada
| | - Jung-Eun Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Housheng Hansen He
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Haiyang Guo
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, China.,Tumor Marker Detection Engineering Laboratory of Shandong Province, Jinan, Shandong, China.,Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
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29
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Kunze B, Middelhoff M, Maurer HC, Agibalova T, Anand A, Bührer AM, Fang HY, Baumeister T, Steiger K, Strangmann J, Schmid RM, Wang TC, Quante M. Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa. Sci Rep 2021; 11:4509. [PMID: 33627749 PMCID: PMC7904766 DOI: 10.1038/s41598-021-84011-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
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Affiliation(s)
- Bettina Kunze
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Moritz Middelhoff
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.
| | - H Carlo Maurer
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Tatiana Agibalova
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Akanksha Anand
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Anne-Marie Bührer
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Hsin-Yu Fang
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Theresa Baumeister
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Julia Strangmann
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Roland M Schmid
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Michael Quante
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany. .,Klinik für Innere Medizin II, Gastrointestinale Onkologie, Universitätsklinikum Freiburg, Freiburg, Germany.
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Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection. Microorganisms 2020; 8:microorganisms8121995. [PMID: 33542169 PMCID: PMC7765114 DOI: 10.3390/microorganisms8121995] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling.
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Abstract
The cardinal properties of adult tissue stem cells are self-renewal and the ability to generate diverse resident cell types. The daily losses of terminally differentiated intestinal, skin, and blood cells require "professional" stem cells to produce replacements. This occurs by continuous expansion of stem cells and their immediate progeny, followed by coordinated activation of divergent transcriptional programs to generate stable cells with diverse functions. Other tissues turn over slowly, if at all, and vary widely in strategies for facultative stem cell activity or interconversion among mature resident cell types (transdifferentiation). Cell fate potential is programmed in tissue-specific configurations of chromatin, which restrict the complement of available genes and cis-regulatory elements, hence allowing specific cell types to arise. Using as a model the transcriptional and chromatin basis of cell differentiation and dedifferentiation in intestinal crypts, we discuss here how self-renewing and other tissues execute homeostatic and injury-responsive stem cell activity.
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Affiliation(s)
- Madhurima Saxena
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; .,Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts 02215, USA.,Current affiliation: Translational Medicine, Bristol-Myers-Squibb, Cambridge, Massachusetts 02142, USA;
| | - Ramesh A Shivdasani
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; .,Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts 02215, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA
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Wang H, Cui G, Yu B, Sun M, Yang H. Cancer Stem Cell Niche in Colorectal Cancer and Targeted Therapies. Curr Pharm Des 2020; 26:1979-1993. [PMID: 32268862 DOI: 10.2174/1381612826666200408102305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/06/2020] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells, are a sub-population of tumor cells found in many human cancers that are endowed with self-renewal and pluripotency. CSCs may be more resistant to conventional anticancer therapies than average cancer cells, as they can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of CSCs remains an unmet clinical need. CSCs are localized in a specialized microenvironment termed the niche, which plays a pivotal role in cancer multidrug resistance. The niche components of CSCs, such as the extracellular matrix, also physically shelter CSCs from therapeutic agents. Colorectal cancer is the most common malignancy worldwide and presents a relatively transparent process of cancer initiation and development, making it an ideal model for CSC niche research. Here, we review recent advances in the field of CSCs using colorectal cancer as an example to illustrate the potential therapeutic value of targeting the CSC niche. These findings not only provide a novel theoretical basis for in-depth discussions on tumor occurrence, development, and prognosis evaluation, but also offer new strategies for the targeted treatment of cancer.
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Affiliation(s)
- Hao Wang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, China.,Laboratory medical college, Jilin Medical University, Jilin, China
| | - Guihua Cui
- School of Pharmacy, Jilin Medical University, Jilin, China
| | - Bo Yu
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, China
| | - Meiyan Sun
- Laboratory medical college, Jilin Medical University, Jilin, China
| | - Hong Yang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, China
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Xiao S, Zhou L. Gastric Stem Cells: Physiological and Pathological Perspectives. Front Cell Dev Biol 2020; 8:571536. [PMID: 33043003 PMCID: PMC7527738 DOI: 10.3389/fcell.2020.571536] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/20/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric epithelium operates in a hazardous environment that curtails the lifespan of the constituent cells, imposing a requirement for continuous epithelial renewal. Stem cells that reside in the stomach are thus essential for regulating physiological tissue renewal and injury repair because of their self-renewal, high proliferation capacity and multiple differentiation potentials. Recent investigations using lineage tracing models have identified diverse populations of gastric stem cells and even fully differentiated cells that can regain stem cell capacity, so enriching our understanding on the identity and plasticity of gastric stem cells. These cell populations include the Villin promotor, Lgr5+, CCKR2+, Axin2+ and AQP5+ stem cells in the antrum, TFF2 mRNA, Mist1+ cells and Troy+ mature chief cells in the corpus, as well as Sox2, eR1, Lrig1, Bmi1-marked cell in both the antrum and the corpus. Establishment of gastric organoids derived from primary gastric tissues and pluripotent stem cells or embryonic stem cells characterizes niche factors required by the gastric stem cell populations, and further provides new insights into stomach development, host-Helicobacter pylori interactions and malignant transformation. Furthermore, focus on the gastric stem cells and their niches uncovers the initiation of stomach precancerous lesions and origin of gastric cancer, providing options for cancer prevention and intervention. In summary, with the development of stem cell research, gastric stem cells give us more opportunities to prevent and treat stomach diseases.
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Affiliation(s)
- Shiyu Xiao
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing, China
| | - Liya Zhou
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing, China
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Sayols S, Klassek J, Werner C, Möckel S, Ritz S, Mendez-Lago M, Soshnikova N. Signalling codes for the maintenance and lineage commitment of embryonic gastric epithelial progenitors. Development 2020; 147:dev.188839. [PMID: 32878924 DOI: 10.1242/dev.188839] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022]
Abstract
The identity of embryonic gastric epithelial progenitors is unknown. We used single-cell RNA-sequencing, genetic lineage tracing and organoid assays to assess whether Axin2- and Lgr5-expressing cells are gastric progenitors in the developing mouse stomach. We show that Axin2 + cells represent a transient population of embryonic epithelial cells in the forestomach. Lgr5 + cells generate both glandular corpus and squamous forestomach organoids ex vivo Only Lgr5 + progenitors give rise to zymogenic cells in culture. Modulating the activity of the WNT, BMP and Notch pathways in vivo and ex vivo, we found that WNTs are essential for the maintenance of Lgr5 + epithelial cells. Notch prevents differentiation of the embryonic epithelial cells along all secretory lineages and hence ensures their maintenance. Whereas WNTs promote differentiation of the embryonic progenitors along the zymogenic cell lineage, BMPs enhance their differentiation along the parietal lineage. In contrast, WNTs and BMPs are required to suppress differentiation of embryonic gastric epithelium along the pit cell lineage. Thus, coordinated action of the WNT, BMP and Notch pathways controls cell fate determination in the embryonic gastric epithelium.
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Affiliation(s)
- Sergi Sayols
- Institute of Molecular Biology gGmbH, Mainz 55128, Germany
| | - Jakub Klassek
- Institute of Molecular Biology gGmbH, Mainz 55128, Germany
| | - Clara Werner
- Institute of Molecular Biology gGmbH, Mainz 55128, Germany
| | | | - Sandra Ritz
- Institute of Molecular Biology gGmbH, Mainz 55128, Germany
| | | | - Natalia Soshnikova
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany
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Kunze B, Wein F, Fang HY, Anand A, Baumeister T, Strangmann J, Gerland S, Ingermann J, Münch NS, Wiethaler M, Sahm V, Hidalgo-Sastre A, Lange S, Lightdale CJ, Bokhari A, Falk GW, Friedman RA, Ginsberg GG, Iyer PG, Jin Z, Nakagawa H, Shawber CJ, Nguyen T, Raab WJ, Dalerba P, Rustgi AK, Sepulveda AR, Wang KK, Schmid RM, Wang TC, Abrams JA, Quante M. Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma. Gastroenterology 2020; 159:575-590. [PMID: 32325086 PMCID: PMC7484392 DOI: 10.1053/j.gastro.2020.04.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 03/19/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. METHODS We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. RESULTS Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. CONCLUSIONS Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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Affiliation(s)
- Bettina Kunze
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Frederik Wein
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Hsin-Yu Fang
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Akanksha Anand
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Theresa Baumeister
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Julia Strangmann
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Sophie Gerland
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Jonas Ingermann
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | | | - Maria Wiethaler
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Vincenz Sahm
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Ana Hidalgo-Sastre
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Sebastian Lange
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Charles J Lightdale
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Aqiba Bokhari
- Yosemite Pathology Medical Group, Modesto, California
| | - Gary W Falk
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Richard A Friedman
- Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Gregory G Ginsberg
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Prasad G Iyer
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Zhezhen Jin
- Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York
| | - Hiroshi Nakagawa
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Carrie J Shawber
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York
| | - TheAnh Nguyen
- Oregon Health and Science University, Portland, Oregon
| | - William J Raab
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Piero Dalerba
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, New York
| | - Anil K Rustgi
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Antonia R Sepulveda
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Kenneth K Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Roland M Schmid
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Julian A Abrams
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
| | - Michael Quante
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany.
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Zhang M, Liu Y, Chen YG. Generation of 3D human gastrointestinal organoids: principle and applications. ACTA ACUST UNITED AC 2020; 9:6. [PMID: 32588198 PMCID: PMC7306834 DOI: 10.1186/s13619-020-00040-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023]
Abstract
The stomach and intestine are important organs for food digestion, nutrient absorption, immune protection and hormone production. Gastrointestinal diseases such as cancer and ulcer are big threats to human health. Appropriate disease models are in sore need for mechanistic understanding and drug discovery. Organoids are three-dimensional in vitro cultured structures derived from tissues and pluripotent stem cells with multiple types of cells and mimicking in vivo tissues in major aspects. They have a great potential in regenerative medicine and personalized medicine. Here, we review the major signaling pathways regulating gastrointestinal epithelial homeostasis, summarize different methods to generate human gastrointestinal organoids and highlight their applications in biological research and medical practice.
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Affiliation(s)
- Mengxian Zhang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuan Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
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Miao ZF, Adkins-Threats M, Burclaff JR, Osaki LH, Sun JX, Kefalov Y, He Z, Wang ZN, Mills JC. A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation. Cell Stem Cell 2020; 26:910-925.e6. [PMID: 32243780 DOI: 10.1016/j.stem.2020.03.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids. AMPK activation targets Krüppel-like factor 4 (KLF4), known to govern progenitor proliferation and PC fate choice, and PGC1α, which we show controls PC maturation after their specification. PC-specific deletion of AMPKα or PGC1α causes defective PC maturation, which could not be rescued by metformin. However, metformin treatment still increases KLF4 levels and suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitors to reduce self-renewal and promote PC fate, whereas AMPK-PGC1α activation within the PC lineage promotes maturation, providing a potential suggestion for why metformin increases acid secretion and reduces gastric cancer risk in humans.
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Affiliation(s)
- Zhi-Feng Miao
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
| | - Mahliyah Adkins-Threats
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Joseph R Burclaff
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Luciana H Osaki
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jing-Xu Sun
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
| | - Yan Kefalov
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Zheng He
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Radiation Oncology, First Hospital of China Medical University, Shenyang, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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Baratta V, Own J, Di Renzo C, Ollodart J, Geibel JP, Barahona M. In Pursuit of the Parietal Cell - An Evolution of Scientific Methodology and Techniques. Front Physiol 2019; 10:1497. [PMID: 31920702 PMCID: PMC6920182 DOI: 10.3389/fphys.2019.01497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/25/2019] [Indexed: 11/30/2022] Open
Abstract
The stomach has unique embryologic and anatomic properties, making the study of the parietal cell technically challenging. Numerous individuals have devoted decades of research to unraveling the pathophysiological basis of this cell type. Here, we perform a scoping review of novel in vitro and in vivo methodology pertaining to the parietal cell. First, we evaluate early in vitro methods of parietal cell analysis. This section focuses on three major techniques: gastric gland isolation, parietal cell isolation, and parietal cell culture. We also discuss parietal cell physiology and pathophysiology. Second, we discuss more contemporary efforts involving confocal microscopy and gastric organoids, a new technique that holds much promise in unveiling the temporal-spatial dynamics of the cell. Finally, we will discuss findings from our laboratory where we identified an active gastric vacuolar H+-ATPase as a putative mechanism for refractory GERD. Overall, this review aims to highlight the major milestones in understanding an elusive yet important cell. Though in no way comprehensive, we hope to provide a birds-eye view to the study of this unique cell type in the gastrointestinal tract.
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Affiliation(s)
- Vanessa Baratta
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - Jason Own
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - Chiara Di Renzo
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University, Padua, Italy
| | - Jenna Ollodart
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - John P. Geibel
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
| | - Maria Barahona
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
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Francis R, Guo H, Streutker C, Ahmed M, Yung T, Dirks PB, He HH, Kim TH. Gastrointestinal transcription factors drive lineage-specific developmental programs in organ specification and cancer. SCIENCE ADVANCES 2019; 5:eaax8898. [PMID: 31844668 PMCID: PMC6905862 DOI: 10.1126/sciadv.aax8898] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 10/16/2019] [Indexed: 05/09/2023]
Abstract
Transcription factors (TFs) are spatially and temporally regulated during gut organ specification. Although accumulating evidence shows aberrant reactivation of developmental programs in cancer, little is known about how TFs drive lineage specification in development and cancer. We first defined gastrointestinal tissue-specific chromatin accessibility and gene expression during development, identifying the dynamic epigenetic regulation of SOX family of TFs. We revealed that Sox2 is not only essential for gastric specification, by maintaining chromatin accessibility at forestomach lineage loci, but also sufficient to promote forestomach/esophageal transformation upon Cdx2 deletion. By comparing our gastrointestinal lineage-specific transcriptome to human gastrointestinal cancer data, we found that stomach and intestinal lineage-specific programs are reactivated in Sox2high /Sox9high and Cdx2high cancers, respectively. By analyzing mice deleted for both Sox2 and Sox9, we revealed their potentially redundant roles in both gastric development and cancer, highlighting the importance of developmental lineage programs reactivated by gastrointestinal TFs in cancer.
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Affiliation(s)
- Roshane Francis
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Haiyang Guo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - Catherine Streutker
- Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, Ontario M5B 1W8, Canada
| | - Musaddeque Ahmed
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada
| | - Theodora Yung
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Peter B. Dirks
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Housheng Hansen He
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada
- Corresponding author. (T.-H.K.); (H.H.H.)
| | - Tae-Hee Kim
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Corresponding author. (T.-H.K.); (H.H.H.)
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Downregulation of Notch Signaling in Kras-Induced Gastric Metaplasia. Neoplasia 2019; 21:810-821. [PMID: 31276933 PMCID: PMC6611983 DOI: 10.1016/j.neo.2019.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/28/2019] [Accepted: 06/04/2019] [Indexed: 11/21/2022] Open
Abstract
Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer. Expression of mutant KrasG12D in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia. However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood. Here we report that KrasLSL-G12D/+;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates KrasG12D expression in the stomach, causing gastric hyperplasia and metaplasia prior to the pathologic changes in the pancreas. These mice exhibit ectopic cell proliferation at the base of gastric glands, whereas wild-type mice contain proliferating cells primarily at the isthmus/neck of the gastric glands. Notch signaling is decreased in the KrasLSL-G12D/+;Pdx1-cre gastric mucosa, as shown by lower levels of cleaved Notch intracellular domains and downregulation of Notch downstream target genes. Expression of a Notch ligand Jagged1 is downregulated at the base of the mutant gland, accompanied by loss of chief cell marker Mist1. We demonstrate that exogenous Jagged1 or overexpression of Notch intracellular domain stimulates Mist1 expression in gastric cancer cell lines, suggesting positive regulation of Mist1 by Notch signaling. Finally, deletion of Jagged1 or Notch3 in KrasLSL-G12D/+;Pdx1-cre mice promoted development of squamous cell carcinoma in the forestomach, albeit short of invasive adenocarcinoma in the glandular stomach. Taken together, these results reveal downregulation of Notch signaling and Mist1 expression during the initiation of Kras-driven gastric tumorigenesis and suggest a tumor-suppressive role for Notch in this context.
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Xiu MX, Liu YM. The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. Am J Cancer Res 2019; 9:837-854. [PMID: 31218097 PMCID: PMC6556604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 04/22/2019] [Indexed: 06/09/2023] Open
Abstract
Deregulated Notch signaling is a key factor thought to facilitate the stem-like proliferation of cancer cells, thereby facilitating disease progression. Four subtypes of Notch receptor have been described to date, with each playing a distinct role in cancer development and progression, therefore warranting a careful and comprehensive examination of the targeting of each receptor subtype in the context of oncogenesis. Clinical efforts to translate the DAPT, which blocks Notch signaling, have been unsuccessful due to a combination of serious gastrointestinal side effects and a lack of complete blocking efficacy. There is therefore a clear need to identify better therapeutic strategies for targeting and manipulating Notch signaling. Notch2 is a Notch receptor that is commonly overexpressed in a range of cancers, and which is linked to a unique oncogenic mechanism. Successful efforts to block Notch2 signaling will depend upon doing so both efficiently and specifically in patients. As such, in the present review we will explore the role of Notch2 signaling in the development and progression of cancer, and we will assess agents and strategies with the potential to effectively disrupt Notch2 signaling and thereby yield novel cancer treatment regimens.
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Affiliation(s)
- Meng-Xi Xiu
- Medical School of Nanchang University Nanchang, Jiangxi, China
| | - Yuan-Meng Liu
- Medical School of Nanchang University Nanchang, Jiangxi, China
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43
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Li X, Zhang C, Gong T, Ni X, Li J, Zhan D, Liu M, Song L, Ding C, Xu J, Zhen B, Wang Y, Qin J. A time-resolved multi-omic atlas of the developing mouse stomach. Nat Commun 2018; 9:4910. [PMID: 30464175 PMCID: PMC6249217 DOI: 10.1038/s41467-018-07463-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023] Open
Abstract
The mammalian stomach is structurally highly diverse and its organ functionality critically depends on a normal embryonic development. Although there have been several studies on the morphological changes during stomach development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive, temporal proteome and transcriptome atlas of the mouse stomach at multiple developmental stages. Quantitative analysis of 12,108 gene products allows identifying three distinct phases based on changes in proteins and RNAs and the gain of stomach functions on a longitudinal time scale. The transcriptome indicates functionally important isoforms relevant to development and identifies several functionally unannotated novel splicing junction transcripts that we validate at the peptide level. Importantly, many proteins differentially expressed in stomach development are also significantly overexpressed in diffuse-type gastric cancer. Overall, our study provides a resource to understand stomach development and its connection to gastric cancer tumorigenesis.
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Affiliation(s)
- Xianju Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Chunchao Zhang
- Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Tongqing Gong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Xiaotian Ni
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China.,Department of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jin'e Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Dongdong Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China.,Department of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Mingwei Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Lei Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, and School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, 100071, China
| | - Bei Zhen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Yi Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China. .,Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Jun Qin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China. .,Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .,State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, and School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
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44
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Hata M, Hayakawa Y, Koike K. Gastric Stem Cell and Cellular Origin of Cancer. Biomedicines 2018; 6:biomedicines6040100. [PMID: 30384487 PMCID: PMC6315982 DOI: 10.3390/biomedicines6040100] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 10/28/2018] [Accepted: 10/28/2018] [Indexed: 12/16/2022] Open
Abstract
Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that Lgr5+ cells in the gut are the origin of gastrointestinal cancers. Reserve or facultative stem or progenitor cells with the ability to convert to Lgr5+ cells following injury have also been identified. Unlike the intestine, where Lgr5+ cells at the crypt base act as active stem cells, the stomach may contain unique stem cell populations, since gastric Lgr5+ 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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Affiliation(s)
- Masahiro Hata
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 1138655, Japan.
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 1138655, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 1138655, Japan.
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Huang JP, Lin J, Tzen CY, Huang WY, Tsai CC, Chen CJ, Lu YJ, Chou KF, Su YW. FANCA D1359Y mutation in a patient with gastric polyposis and cancer susceptibility: A case report and review of literature. World J Gastroenterol 2018; 24:4412-4418. [PMID: 30344425 PMCID: PMC6189845 DOI: 10.3748/wjg.v24.i38.4412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 08/02/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric polyposis is a rare disease. Not all polyps progress to cancer. Monoallelic mutation in Fanconi anemia (FA) genes, unlike biallelic gene mutations that causes typical FA phenotype, can increase risks of cancers in a sporadic manner. Aberrations in the FA pathway were reported in all molecular subtypes of gastric cancer. We studied a patient with synchronous gastric cancer from gastric polyposis by conducting a 13-year long-term follow up. Via pathway-driven massive parallel genomic sequencing, a germline mutation at FANCA D1359Y was identified. We identified several recurrent mutations in DNA methylation (TET1, V873I), the β-catenin pathway (CTNNB1, S45F) and RHO signaling pathway (PLEKHG5, R203C) by comparing the genetic events between benign and malignant gastric polyps. Furthermore, we revealed gastric polyposis susceptible genes and genetic events promoting malignant transformation using pathway-driven targeted gene sequencing.
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Affiliation(s)
- Jeffrey Peng Huang
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10491, Taiwan
| | - Johnson Lin
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10491, Taiwan
| | - Chi-Yuan Tzen
- Department of Pathology, Mackay Memorial Hospital, Taipei 10491, Taiwan
| | - Wen-Yu Huang
- Laboratory of Good Clinical Research Center, Mackay Memorial Hospital, Tamsui Branch, New Taipei City 25160, Taiwan
| | - Chia-Chi Tsai
- Department of General Surgery, Mackay Memorial Hospital, Taipei 10491, Taiwan
| | - Chih-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10491, Taiwan
| | - Yen-Jung Lu
- ACT Genomics Co., Ltd., Taipei 11494, Taiwan
| | - Kuei-Fang Chou
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10491, Taiwan
| | - Ying-Wen Su
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10491, Taiwan
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46
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Dai Q, Duan C, Ren W, Li F, Zheng Q, Wang L, Li W, Lu X, Ni W, Zhang Y, Chen Y, Wen T, Yu Y, Yu H. Notch Signaling Regulates Lgr5 + Olfactory Epithelium Progenitor/Stem Cell Turnover and Mediates Recovery of Lesioned Olfactory Epithelium in Mouse Model. Stem Cells 2018; 36:1259-1272. [PMID: 29664186 DOI: 10.1002/stem.2837] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 03/28/2018] [Accepted: 04/06/2018] [Indexed: 12/18/2022]
Abstract
The Notch signaling pathway regulates stem cell proliferation and differentiation in multiple tissues and organs, and is required for tissue maintenance. However, the role of Notch in regulation of olfactory epithelium (OE) progenitor/stem cells to maintain tissue function is still not clear. A recent study reported that leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in globose basal cells (GBCs) localized in OE. Through lineage tracing in vivo, we found that Lgr5+ cells act as progenitor/stem cells in OE. The generation of daughter cells from Lgr5+ progenitor/stem cells is delicately regulated by the Notch signaling pathway, which not only controls the proliferation of Lgr5+ cells and their immediate progenies but also affects their subsequent terminal differentiation. In conditionally cultured OE organoids in vitro, inhibition of Notch signaling promotes neuronal differentiation. Besides, OE lesion through methimazole administration in mice induces generation of more Notch1+ cells in the horizontal basal cell (HBC) layer, and organoids derived from lesioned OE possesses more proliferative Notch1+ HBCs. In summary, we concluded that Notch signaling regulates Lgr5+ GBCs by controlling cellular proliferation and differentiation as well as maintaining epithelial cell homeostasis in normal OE. Meanwhile, Notch1 also marks HBCs in lesioned OE and Notch1+ HBCs are transiently present in OE after injury. This implies that Notch1+ cells in OE may have dual roles, functioning as GBCs in early development of OE and HBCs in restoring the lesioned OE. Stem Cells 2018;36:1259-1272.
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Affiliation(s)
- Qi Dai
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Chen Duan
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Wenwen Ren
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Fangqi Li
- School of Life Sciences, Shanghai University, Shanghai, People's Republic of China
| | - Qian Zheng
- School of Life Sciences, Shanghai University, Shanghai, People's Republic of China
| | - Li Wang
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Wenyan Li
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Xiaoling Lu
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Wenli Ni
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Yanping Zhang
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Yan Chen
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
| | - Tieqiao Wen
- School of Life Sciences, Shanghai University, Shanghai, People's Republic of China
| | - Yiqun Yu
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China.,School of Life Sciences, Shanghai University, Shanghai, People's Republic of China
| | - Hongmeng Yu
- Department of Otolaryngology, Eye, Ear, Nose & Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, People's Republic of China
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47
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Kang M, Zhang Y, Jin X, Chen G, Huang Y, Wu D, Li G, Shan J, Huang P, Chen J. Concurrent Treatment with Anti-DLL4 Enhances Antitumor and Proapoptotic Efficacy of a γ-Secretase Inhibitor in Gastric Cancer. Transl Oncol 2018; 11:599-608. [PMID: 29571073 PMCID: PMC6002351 DOI: 10.1016/j.tranon.2018.02.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/14/2018] [Accepted: 02/19/2018] [Indexed: 02/07/2023] Open
Abstract
The Notch signaling pathway has been identified as a therapeutic target for cancers. γ-Secretase inhibitors (GSIs) have been progressively recognized as potential anticancer drugs. The present study aimed to investigate the effects of anti-delta like legend 4 (anti-DLL4) treatment on the anticancer efficacy of GSIs in gastric cancer. SGC-7901-GFP human gastric cancer cells were tested for DLL4 expression by rosette formation test and immunofluorescence, and then were treated with anti-DLL4 antibody N-[N-(3,5-difluorophenacetyl)-L-ananyl]-S-phenylglycine t-butyl ester (DAPT, a type of GSI), or a combination of anti-DLL4 antibody and DAPT. The effects of in vitro treatments on cell apoptosis, cell cycle, and cell invasion were analyzed. For in vivo study, an orthotopic mouse model of gastric cancer was established with green fluorescence expressing SGC-7901. Ultrasound targeted microbubble destruction was used to treat tumor-bearing mice with anti-DLL4 antibody conjugated microbubbles, DAPT, and a combination of the two. Real-time fluorescence imaging was performed to assess tumor cell inhibition in each group. Following in vivo treatments, apoptosis of tumor cells and the expression of apoptosis-related genes BAX, Bcl-2, and P53 were detected by TUNEL and immunohistochemical staining. In vivo combined treatment of anti-DLL4 and DAPT led to a higher rate of cell apoptosis and greater inhibition of cell invasion than that observed with DAPT treatment alone. DAPT and anti-DLL4 combination therapy resulted in decreased cell distribution at G1 phase and increased cell distribution at S phase, compared to the untreated control group (P < .01). In vivo combined therapy with anti-DLL4 and DAPT significantly increased tumor growth inhibition and tumor cell apoptosis when compared to DAPT therapy alone (P < .05). In addition, combined treatment significantly increased expression of BAX and P53 and reduced Bcl-2 expression (P < .05). Conversely, treatment with DAPT alone only increased expression of BAX and P53 (P < .05), suggesting that the reduction of Bcl-2 expression may play an important role in the synergetic antitumor and proapoptosis effects of the combined treatment. Concurrent treatment with anti-DLL4 enhances the antitumor and proapoptotic efficacy of the γ-secretase inhibitor in gastric cancer both in vitro and in vivo.
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Affiliation(s)
- Muxing Kang
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China; Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Yaoyi Zhang
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Xiaoli Jin
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Guofeng Chen
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Yi Huang
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Dan Wu
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Guogang Li
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Jianzhen Shan
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
| | - Pintong Huang
- Department of Radiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China.
| | - Jian Chen
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China.
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48
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Li L, Li Y, Wang L, Wu Z, Ma H, Shao J, Li D, Yu H, Nian W, Wang D. Inhibition of Hes1 enhances lapatinib sensitivity in gastric cancer sphere-forming cells. Oncol Lett 2017; 14:3989-3996. [PMID: 28959362 PMCID: PMC5607651 DOI: 10.3892/ol.2017.6683] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 05/26/2017] [Indexed: 01/26/2023] Open
Abstract
It has been considered that the neurogenic locus notch homolog protein (Notch) signaling pathway serves an essential role in cellular differentiation, proliferation and apoptosis. However, the function of the Notch signaling pathway in gastric cancer stem cells (GCSCs) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sensitivity remains unclear. The present study aimed to delineate the role of the Notch1 signaling pathway in GCSCs and lapatinib sensitivity. Sphere-forming cells were separated from human gastric cancer MKN45 parental cells. The sphere-forming cells exhibited characteristics of CSCs and higher Notch1 expression compared with that of parental cells. To investigate the role of the Notch1 signaling pathway in GCSCs, the expression of transcription factor Hes1 (Hes1) was knocked down using small interfering RNA against Hes1. It was observed that Hes1 expression was significantly downregulated in knocked down cells. The inhibition of Hes1 suppressed the properties of CSCs, as indicated by significant decreases in the expression of the transcription factor sex determining region Y-box 2, epithelial cell adhesion molecule and the homeobox protein Nanog and reduced spheroid colony formation. In addition, epithelial-mesenchymal transition was significantly impaired in sphere-forming cells following Hes1 knockdown. Furthermore, the inhibition of Hes1 effectively enhanced lapatinib sensitivity in sphere-forming cells. These results suggest that sphere-forming gastric cancer cells possess the characteristics of CSCs, and that the Notch1 signaling pathway serves an essential role in the maintenance of CSCs and lapatinib sensitivity.
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Affiliation(s)
- Luchun Li
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Yan Li
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Lulu Wang
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Zhijuan Wu
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Huiwen Ma
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Jianghe Shao
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Dairong Li
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Huiqing Yu
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Weiqi Nian
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
| | - Donglin Wang
- Department of Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing 400030, P.R. China
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49
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Piccolo P, Attanasio S, Secco I, Sangermano R, Strisciuglio C, Limongelli G, Miele E, Mutarelli M, Banfi S, Nigro V, Pons T, Valencia A, Zentilin L, Campione S, Nardone G, Lynnes TC, Celestino-Soper PBS, Spoonamore KG, D'Armiento FP, Giacca M, Staiano A, Vatta M, Collesi C, Brunetti-Pierri N. MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy. Hum Mol Genet 2017; 26:33-43. [PMID: 28013292 DOI: 10.1093/hmg/ddw365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 10/19/2016] [Indexed: 12/30/2022] Open
Abstract
We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Ménétrier disease.
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Affiliation(s)
- Pasquale Piccolo
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Sergio Attanasio
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Ilaria Secco
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Riccardo Sangermano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialized Surgery, Second University of Naples, Naples, Italy
| | - Giuseppe Limongelli
- Department of Cardiothoracic Sciences, Monaldi Hospital, Second University of Naples, Naples, Italy
| | - Erasmo Miele
- Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy
| | | | - Sandro Banfi
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.,Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Vincenzo Nigro
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.,Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Tirso Pons
- Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Alfonso Valencia
- Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Lorena Zentilin
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Severo Campione
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Gerardo Nardone
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy
| | - Ty C Lynnes
- Department of Medical and Molecular Genetics
| | | | - Katherine G Spoonamore
- Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Mauro Giacca
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.,Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Annamaria Staiano
- Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy
| | - Matteo Vatta
- Department of Medical and Molecular Genetics.,Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chiara Collesi
- Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.,Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Nicola Brunetti-Pierri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.,Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy
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50
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Chen X, Liao R, Li D, Sun J. Induced cancer stem cells generated by radiochemotherapy and their therapeutic implications. Oncotarget 2017; 8:17301-17312. [PMID: 28038467 PMCID: PMC5370042 DOI: 10.18632/oncotarget.14230] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 12/13/2016] [Indexed: 12/26/2022] Open
Abstract
Local and distant recurrence of malignant tumors following radio- and/or chemotherapy correlates with poor prognosis of patients. Among the reasons for cancer recurrence, preexisting cancer stem cells (CSCs) are considered the most likely cause due to their properties of self-renewal, pluripotency, plasticity and tumorigenicity. It has been demonstrated that preexisting cancer stem cells derive from normal stem cells and differentiated somatic cells that undergo transformation and dedifferentiation respectively under certain conditions. However, recent studies have revealed that cancer stem cells can also be induced from non-stem cancer cells by radiochemotherapy, constituting the subpopulation of induced cancer stem cells (iCSCs). These findings suggest that radiochemotherapy has the side effect of directly transforming non-stem cancer cells into induced cancer stem cells, possibly contributing to tumor recurrence and metastasis. Therefore, drugs targeting cancer stem cells or preventing dedifferentiation of non-stem cancer cells can be combined with radiochemotherapy to improve its antitumor efficacy. The current review is to investigate the mechanisms by which induced cancer stem cells are generated by radiochemotherapy and hence provide new strategies for cancer treatment.
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Affiliation(s)
- Xiewan Chen
- Medical English Department, College of Basic Medicine, Third Military Medical University, Chongqing, China.,Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Rongxia Liao
- Medical English Department, College of Basic Medicine, Third Military Medical University, Chongqing, China
| | - Dezhi Li
- Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jianguo Sun
- Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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