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1
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Mortoglou M, Lian M, Miralles F, Dart DA, Uysal-Onganer P. miR-210 Mediated Hypoxic Responses in Pancreatic Ductal Adenocarcinoma. ACS OMEGA 2024; 9:47872-47883. [PMID: 39651070 PMCID: PMC11618397 DOI: 10.1021/acsomega.4c08947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 12/11/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one among the most lethal malignancies due to its aggressive behavior and resistance to conventional therapies. Hypoxia significantly contributes to cancer progression and therapeutic resistance of PDAC. microRNAs (miRNAs/miRs) have emerged as critical regulators of various biological processes. miR-210 is known as the "hypoxamir" due to its prominent role in cellular responses to hypoxia. In this study, we investigated the multifaceted role of miR-210 in PDAC using miR-210 knockout (KO) cellular models to elucidate its functions under hypoxic conditions. Hypoxia-inducible factor-1α (HIF1-α), a key transcription factor activated in response to low oxygen levels, upregulates miR-210. miR-210 maintains cancer stem cell (CSC) phenotypes and promotes epithelial-mesenchymal transition (EMT), which is essential for tumor initiation, metastasis, and therapeutic resistance. Our findings demonstrate that miR-210 regulates the expression of CSC markers, such as CD24, CD44, and CD133, and EMT markers, including E-cadherin, Vimentin, and Snail. Specifically, depletion of miR-210 reversed EMT and CSC marker expression levels in hypoxic Panc-1 and MiaPaCa-2 PDAC cells. These regulatory actions facilitate a more invasive and treatment-resistant PDAC phenotype. Understanding the regulatory network involving miR-210 under hypoxic conditions may reveal new therapeutic targets for combating PDAC and improving patient outcomes. Our data suggest that miR-210 is a critical regulator of HIF1-α expression, EMT, and the stemness of PDAC cells in hypoxic environments.
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Affiliation(s)
- Maria Mortoglou
- Cancer
Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, U.K.
| | - Mutian Lian
- Cancer
Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, U.K.
| | - Francesc Miralles
- School
of Health and Medical Sciences, City St
George’s, University of London, Cranmer Terrace, London SW17 0RE, U.K.
| | - D. Alwyn Dart
- UCL
Cancer Institute, University College London, Paul O’Gorman Building, 72
Huntley Street, London WC1E 6DD, U.K.
| | - Pinar Uysal-Onganer
- Cancer
Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, U.K.
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2
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Chung WC, Xu K. Notch signaling pathway in pancreatic tumorigenesis. Adv Cancer Res 2023. [DOI: 10.1016/bs.acr.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
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3
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Li C, Xie Z, Xing Z, Zhu H, Zhou W, Xie S, Zhang Z, Li MH. The Notch Signaling Pathway Regulates Differentiation of NG2 Cells into Oligodendrocytes in Demyelinating Diseases. Cell Mol Neurobiol 2022; 42:1-11. [PMID: 33826017 PMCID: PMC11421596 DOI: 10.1007/s10571-021-01089-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/29/2021] [Indexed: 12/13/2022]
Abstract
NG2 cells are highly proliferative glial cells that can self-renew or differentiate into oligodendrocytes, promoting remyelination. Following demyelination, the proliferative and differentiation potentials of NG2 cells increase rapidly, enhancing their differentiation into functional myelinating cells. Levels of the transcription factors Olig1 and Olig2 increase during the differentiation of NG2 cells and play important roles in the development and repair of oligodendrocytes. However, the ability to generate new oligodendrocytes is hampered by injury-related factors (e.g., myelin fragments, Wnt and Notch signaling components), leading to failed differentiation and maturation of NG2 cells into oligodendrocytes. Here, we review Notch signaling as a negative regulator of oligodendrocyte differentiation and discuss the extracellular ligands, intracellular pathways, and key transcription factors involved.
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Affiliation(s)
- Chengcai Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Zhiping Xie
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Zelong Xing
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Huaxin Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Wu Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Shenke Xie
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Zhixiong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Mei-Hua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, People's Republic of China.
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4
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Palamaris K, Felekouras E, Sakellariou S. Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance. Cancers (Basel) 2021; 13:cancers13215532. [PMID: 34771695 PMCID: PMC8582651 DOI: 10.3390/cancers13215532] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/31/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma’s (PDAC) dismal prognosis is associated with its aggressive biological behavior and resistance to chemotherapy. Epithelial to mesenchymal transition (EMT) has been recognized as a key driver of PDAC progression and development of drug resistance. EMT is a transient and reversible process leading to transdifferentiation of epithelial cells into a more mesenchymal phenotype. It is regulated by multiple signaling pathways that control the activity of a transcription factors network. Activation of EMT in pre-invasive stages of PDAC has been accused for early dissemination. Furthermore, it contributes to the development of intratumoral heterogeneity and drug resistance. This review summarizes the available data regarding signaling networks regulating EMT and describes the integral role of EMT in different aspects of PDAC pathogenesis. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.
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Affiliation(s)
- Kostas Palamaris
- 1ST Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Evangelos Felekouras
- 1ST Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stratigoula Sakellariou
- 1ST Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Correspondence:
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5
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Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition. Biomolecules 2021; 11:biom11070956. [PMID: 34209658 PMCID: PMC8301972 DOI: 10.3390/biom11070956] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities.
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Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy. Molecules 2021; 26:molecules26040972. [PMID: 33673088 PMCID: PMC7917912 DOI: 10.3390/molecules26040972] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/04/2021] [Accepted: 02/09/2021] [Indexed: 12/26/2022] Open
Abstract
The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer's disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.
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7
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Georgakopoulos-Soares I, Chartoumpekis DV, Kyriazopoulou V, Zaravinos A. EMT Factors and Metabolic Pathways in Cancer. Front Oncol 2020; 10:499. [PMID: 32318352 PMCID: PMC7154126 DOI: 10.3389/fonc.2020.00499] [Citation(s) in RCA: 216] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/19/2020] [Indexed: 12/11/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.
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Affiliation(s)
- Ilias Georgakopoulos-Soares
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States.,Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, United States
| | - Dionysios V Chartoumpekis
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Venetsana Kyriazopoulou
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Apostolos Zaravinos
- College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.,Department of Life Sciences European University Cyprus, Nicosia, Cyprus
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8
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Ye J, Wen J, Ning Y, Li Y. Higher notch expression implies poor survival in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Pancreatology 2018; 18:954-961. [PMID: 30297095 DOI: 10.1016/j.pan.2018.09.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 09/26/2018] [Accepted: 09/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND At present, pancreatic ductal adenocarcinoma (PDAC) is a fetal disease lack of effective prognostic and therapeutic methods resulting in high mortality. The Notch signaling has been demonstrated being up- or down-regulated in many cancers, but the effects in pancreatic ductal adenocarcinoma are still controversial. Moreover, the available cases in an individual study are of small samples. Therefore, it is essential to define the effect of Notch signaling in pancreatic ductal adenocarcinoma with larger samples. METHODS Conducted from 6 eligible studies and 463 pancreatic ductal adenocarcinoma patients, this was the first meta-analysis to analyze the correlation between the Notch signal pathway and pancreatic ductal adenocarcinoma. All data were sourced from The National Center for Biotechnology Information, Web of Science and Cochrane. The articles which matched the inclusion criteria were included. All included data were analyzed and performed by Review Manager 5.3. RESULTS The results indicated that high expression of Notch signaling proteins was associated with poor overall survival of pancreatic ductal adenocarcinoma patients (pooled hazard ratio>2.00; P < 0.001). Moreover, poor survival was related to high expression of Notch3 (pooled hazard ratio: 2.05; confidence interval: 1.49-2.82; P < 0.001) and DLL4 (pooled hazard ratio: 2.13; confidence interval: 1.37-3.32; P < 0.001). CONCLUSIONS This meta-analysis supports that Notch signaling proteins may be available as prognostic factors for pancreatic ductal adenocarcinoma progression and patient survival. Higher expression of Notch signaling proteins indicated poor survival of pancreatic ductal adenocarcinoma patients. Targeting Notch signaling components, especially Notch3 protein, would be beneficial for therapies.
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Affiliation(s)
- Jianbin Ye
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Junjie Wen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
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9
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Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH. Cell Death Discov 2018; 4:22. [PMID: 30109141 PMCID: PMC6078940 DOI: 10.1038/s41420-018-0087-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/10/2018] [Indexed: 01/09/2023] Open
Abstract
The incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.
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10
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Janghorban M, Xin L, Rosen JM, Zhang XHF. Notch Signaling as a Regulator of the Tumor Immune Response: To Target or Not To Target? Front Immunol 2018; 9:1649. [PMID: 30061899 PMCID: PMC6055003 DOI: 10.3389/fimmu.2018.01649] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 07/04/2018] [Indexed: 01/05/2023] Open
Abstract
The Notch signaling pathway regulates important cellular processes involved in stem cell maintenance, proliferation, development, survival, and inflammation. These responses to Notch signaling involving both canonical and non-canonical pathways can be spatially and temporally variable and are highly cell-type dependent. Notch signaling can elicit opposite effects in regulating tumorigenicity (tumor-promoting versus tumor-suppressing function) as well as controlling immune cell responses. In various cancer types, Notch signaling elicits a "cancer stem cell (CSC)" phenotype that results in decreased proliferation, but resistance to various therapies, hence potentially contributing to cell dormancy and relapse. CSCs can reshape their niche by releasing paracrine factors and inflammatory cytokines, and the niche in return can support their quiescence and resistance to therapies as well as the immune response. Moreover, Notch signaling is one of the key regulators of hematopoiesis, immune cell differentiation, and inflammation and is implicated in various autoimmune diseases, carcinogenesis (leukemia), and tumor-induced immunosuppression. Notch can control the fate of various T cell types, including Th1, Th2, and the regulatory T cells (Tregs), and myeloid cells including macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs). Both MDSCs and Tregs play an important role in supporting tumor cells (and CSCs) and in evading the immune response. In this review, we will discuss how Notch signaling regulates multiple aspects of the tumor-promoting environment by elucidating its role in CSCs, hematopoiesis, normal immune cell differentiation, and subsequently in tumor-supporting immunogenicity.
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Affiliation(s)
- Mahnaz Janghorban
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
| | - Li Xin
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
| | - Jeffrey M. Rosen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
| | - Xiang H.-F. Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- McNair Medical Institute, Baylor College of Medicine, Houston, TX, United States
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11
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Chen Y, Tan W, Wang C. Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial-mesenchymal transition. Onco Targets Ther 2018; 11:3817-3826. [PMID: 30013362 PMCID: PMC6038883 DOI: 10.2147/ott.s168317] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cancer stem cells are a small population of cells with the potential for self-renewal and multi-directional differentiation and are an important source of cancer initiation, treatment resistance, and recurrence. Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells lose their epithelial phenotype and convert to mesenchymal cells. Recent studies have shown that cancer cells undergoing EMT can become stem-like cells. Many kinds of tumors are associated with chronic inflammation, which plays a role in tumor progression. Among the various immune cells mediating chronic inflammation, macrophages account for ~30%-50% of the tumor mass. Macrophages are highly infiltrative in the tumor microenvironment and secrete a series of inflammatory factors and cytokines, such as transforming growth factor (TGF)-β, IL-6, IL-10, and tumor necrosis factor (TNF)-α, which promote EMT and enhance the stemness of cancer cells. This review summarizes and discusses recent research findings on some specific mechanisms of tumor-associated macrophage-derived cytokines in EMT and cancer stemness transition, which are emerging targets of cancer treatment.
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Affiliation(s)
- Yongxu Chen
- Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, Guangdong Province, People's Republic of China, .,School of Medicine, South China University of Technology, Guangzhou, Guangdong Province, People's Republic of China,
| | - Wei Tan
- Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, Guangdong Province, People's Republic of China,
| | - Changjun Wang
- Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, Guangdong Province, People's Republic of China, .,School of Medicine, South China University of Technology, Guangzhou, Guangdong Province, People's Republic of China,
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12
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Mukherjee N, Almeida A, Partyka KA, Lu Y, Schwan JV, Lambert K, Rogers M, Robinson WA, Robinson SE, Applegate AJ, Amato CM, Luo Y, Fujita M, Norris DA, Shellman YG. Combining a GSI and BCL-2 inhibitor to overcome melanoma's resistance to current treatments. Oncotarget 2018; 7:84594-84607. [PMID: 27829238 PMCID: PMC5356684 DOI: 10.18632/oncotarget.13141] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/27/2016] [Indexed: 12/14/2022] Open
Abstract
Major limitations of current melanoma treatments are for instances of relapse and the lack of therapeutic options for BRAF wild-type patients who do not respond to immunotherapy. Many studies therefore focus on killing resistant subpopulations, such as Melanoma Initiating Cells (MICs) to prevent relapse. Here we examined whether combining a GSI (γ-Secretase Inhibitor) with ABT-737 (a small molecule BCL-2/BCL-XL/BCL-W inhibitor) can kill both the non-MICs (bulk of melanoma) and MICs. To address the limitations of melanoma therapies, we included multiple tumor samples of patients relapsed from current treatments, with a diverse genetic background (with or without the common BRAF, NRAS or NF1 mutations) in these studies. Excitingly, the combination treatment reduced cell viability and induced apoptosis of the non-MICs; disrupted primary spheres, decreased the ALDH+ cells, and inhibited the self-renewability of the MICs in multiple melanoma cell lines and relapsed patient samples. Using a low-cell-number mouse xenograft model, we demonstrated that the combination significantly reduced the tumor initiating ability of MIC-enriched cultures from relapsed patient samples. Mechanistic studies also indicate that cell death is NOXA-dependent. In summary, this combination may be a promising strategy to address treatment relapse and for triple wild-type patients who do not respond to immunotherapy.
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Affiliation(s)
- Nabanita Mukherjee
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Adam Almeida
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Katie A Partyka
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Yan Lu
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Josianna V Schwan
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Karoline Lambert
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Madison Rogers
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - William A Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Steven E Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Allison J Applegate
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Carol M Amato
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA
| | - Yuchun Luo
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - Mayumi Fujita
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
| | - David A Norris
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.,Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO 80220, USA
| | - Yiqun G Shellman
- University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA
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13
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Amanam I, Chung V. Targeted Therapies for Pancreatic Cancer. Cancers (Basel) 2018; 10:E36. [PMID: 29382159 PMCID: PMC5836068 DOI: 10.3390/cancers10020036] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/15/2018] [Accepted: 01/23/2018] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is the third leading cause of cancer related death and by 2030, it will be second only to lung cancer. We have seen tremendous advances in therapies for lung cancer as well as other solid tumors using a molecular targeted approach but our progress in treating pancreatic cancer has been incremental with median overall survival remaining less than one year. There is an urgent need for improved therapies with better efficacy and less toxicity. Small molecule inhibitors, monoclonal antibodies and immune modulatory therapies have been used. Here we review the progress that we have made with these targeted therapies.
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Affiliation(s)
- Idoroenyi Amanam
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
| | - Vincent Chung
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
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14
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Gao J, Long B, Wang Z. Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res 2017; 7:173-186. [PMID: 28337369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 10/12/2016] [Indexed: 09/28/2022] Open
Abstract
Pancreatic cancer (PC) is one of the highly aggressive malignancies in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of PC, such as JNK, PI3K/AKT, Rho GTPase, Hedgehog (Hh) and Skp2. In recent years, accumulated evidence has demonstrated that Notch signaling pathway plays critical roles in the development and progression of PC. Therefore, in this review we discuss the recent literature regarding the function and regulation of Notch in the pathogenesis of PC. Moreover, we describe that Notch signaling pathway could be down-regulated by its inhibitors or natural compounds, which could be a novel approach for the treatment of PC patients.
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Affiliation(s)
- Jiankun Gao
- Sichuan College of Tranditional Chinese Medicine Mianyang, Sichuan, China
| | - Bo Long
- Department of Infectious Diseases, Mianyang 404 Hospital Mianyang, Sichuan, China
| | - Zhiwei Wang
- The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow UniversitySuzhou 215123, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolMA 02215, USA
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15
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Abbaszadegan MR, Bagheri V, Razavi MS, Momtazi AA, Sahebkar A, Gholamin M. Isolation, identification, and characterization of cancer stem cells: A review. J Cell Physiol 2017; 232:2008-2018. [PMID: 28019667 DOI: 10.1002/jcp.25759] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 12/22/2016] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) or tumor-initiating cells (TICs) as a small subset of neoplastic cells are able to produce a tumor (tumorigenesis), maintain the population of tumorigenic cells (self-renewal), and generate the heterogeneous cells constructing the entire tumor (pluripotency). The research on stationary and circulating CSCs due to resistance to conventional therapies and inability in complete eradication of cancer is critical for developing novel therapeutic strategies for a more effective reduction in the risk of tumor metastasis and cancer recurrence. This review compiles information about different methods of detection and dissociation, side population, cellular markers, and establishment culture of CSCs, as well as characteristics of CSCs such as tumorigenicity, and signaling pathways associated with self-renewal and the capability of the same histological tumor regeneration in various cancers.
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Affiliation(s)
- Mohammad Reza Abbaszadegan
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Bagheri
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahya Shariat Razavi
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Biology, Faculty of Sciences, University of Sistan and Baluchestan, Zahedan, Iran
| | - Amir Abbas Momtazi
- Student Research Committee, Nanotechnology Research Center, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Gholamin
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Laboratory Sciences, Faculty of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Barat S, Chen X, Cuong Bui K, Bozko P, Götze J, Christgen M, Krech T, Malek NP, Plentz RR. Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt-Beta-Catenin Pathways in CD44 + Gastric Cancer Stem Cells. Stem Cells Transl Med 2017; 6:819-829. [PMID: 28186678 PMCID: PMC5442767 DOI: 10.1002/sctm.16-0335] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/19/2016] [Accepted: 10/05/2016] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44+ CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44+ CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44+ CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44+ CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44+ CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44+ CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. Stem Cells Translational Medicine 2017;6:819-829.
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Affiliation(s)
- Samarpita Barat
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
| | - Xi Chen
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
| | - Khac Cuong Bui
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
| | - Przemyslaw Bozko
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
| | - Julian Götze
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
| | | | - Till Krech
- Institute of Pathology, Universitötsklinik Hamburg Eppendorf, Hamburg, Germany
| | - Nisar P Malek
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
| | - Ruben R Plentz
- Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany
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17
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Li Y, Li G, Wang K, Xie YY, Zhou RP, Meng Y, Ding R, Ge JF, Chen FH. Autophagy contributes to 4-Amino-2-Trifluoromethyl-Phenyl Retinate-induced differentiation in human acute promyelocytic leukemia NB4 cells. Toxicol Appl Pharmacol 2017; 319:1-11. [PMID: 28130038 DOI: 10.1016/j.taap.2017.01.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 01/22/2017] [Accepted: 01/23/2017] [Indexed: 12/18/2022]
Abstract
As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in treatment of acute promyelocytic leukemia (APL). However, clinical application of ATRA has limitations. Our previous studies suggested that 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, could induce differentiation of APL cells in vivo and in vitro. To explore the underlying mechanism of ATPR, the effect of ATPR on autophagy of APL cells was observed in the present study. The results showed that the differentiation effect of ATPR on APL cells was accompanied with autophagy induction and PML-RARα degradation via activating Notch1 signaling pathway. Moreover, inhibition of autophagy using 3-methyladenine (3-MA) or small interfering RNA (siRNA) that targets essential autophagy gene ATG5 abrogated the ATPR-induced cell differentiation. Furthermore, when pretreated with DAPT, a γ-secretase inhibitor, the Notch1 signaling pathway was blocked in APL cells, followed by the reduction of ATPR-induced autophagy and differentiation. Taken together, these results suggested that autophagy play an important role in ATPR-induced cell differentiation, which may provide a novel approach to cure APL patients.
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Affiliation(s)
- Yue Li
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Ge Li
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Ke Wang
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Ya-Ya Xie
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Ren-Peng Zhou
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Yao Meng
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Ran Ding
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Jin-Fang Ge
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China
| | - Fei-Hu Chen
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, China.
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18
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Elaskalani O, Razak NBA, Falasca M, Metharom P. Epithelial-mesenchymal transition as a therapeutic target for overcoming chemoresistance in pancreatic cancer. World J Gastrointest Oncol 2017; 9:37-41. [PMID: 28144398 PMCID: PMC5241525 DOI: 10.4251/wjgo.v9.i1.37] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 10/25/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer has one of the worst prognoses among all cancers due to the late manifestation of identifiable symptoms and high resistance to chemo- and radiation therapies. In recent years, a cancer development phase termed epithelial-mesenchymal transition (EMT) has gained increasing research focus. The process is implicated in tumour metastasis, and emerging evidence suggests EMT also contributes or induces chemoresistance in several cancers. Nevertheless, the applicability of therapeutic targeting of EMT faces many challenges. In this mini-review, we summarise the evidence supporting the role of EMT in pancreatic cancer progression, focusing particularly on its association with chemoresistance.
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19
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Heiler S, Wang Z, Zöller M. Pancreatic cancer stem cell markers and exosomes - the incentive push. World J Gastroenterol 2016; 22:5971-6007. [PMID: 27468191 PMCID: PMC4948278 DOI: 10.3748/wjg.v22.i26.5971] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 06/03/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.
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20
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Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov 2016; 15:311-25. [PMID: 26822829 DOI: 10.1038/nrd.2015.13] [Citation(s) in RCA: 265] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype, referred to as epithelial-mesenchymal transition, is a critical process for embryonic development that also occurs in adult life, particularly during tumour progression. Tumour cells undergoing epithelial-mesenchymal transition acquire the capacity to disarm the body's antitumour defences, resist apoptosis and anticancer drugs, disseminate throughout the organism, and act as a reservoir that replenishes and expands the tumour cell population. Epithelial-mesenchymal transition is therefore becoming a target of prime interest for anticancer therapy. Here, we discuss the screening and classification of compounds that affect epithelial-mesenchymal transition, highlight some compounds of particular interest, and address issues related to their clinical application.
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Affiliation(s)
- Fabrizio Marcucci
- Scientific Directorate, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy. Present address: Department of Pharmacological and Biomolecular Sciences, University of Milan, via Trentacoste 2, 20133 Milan, Italy
| | - Giorgio Stassi
- Department of Surgical and Oncological Sciences, University of Palermo, Via del Vespro 131, 90127 Palermo, Italy
| | - Ruggero De Maria
- Scientific Directorate, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy
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21
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Liou GY, Storz P. Strategies to Target Pancreatic Cancer. MOLECULAR TARGETS AND STRATEGIES IN CANCER PREVENTION 2016:1-20. [DOI: 10.1007/978-3-319-31254-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Xiao YF, Yong X, Tang B, Qin Y, Zhang JW, Zhang D, Xie R, Yang SM. Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review). Int J Oncol 2015; 48:437-49. [PMID: 26648421 DOI: 10.3892/ijo.2015.3280] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 10/19/2015] [Indexed: 11/05/2022] Open
Abstract
There is no radical cure for all cancer types. The most frequently used therapies are surgical treatment, radiotherapy and chemotherapy. However, recrudescence, radiation resistance and chemotherapy resistance are the most challenging issues in clinical practice. To address these issues, they should be further studied at the molecular level, and the signaling pathways involved represent a promising avenue for this research. In the present review, we mainly discuss the components and mechanisms of activation of the Notch and Wnt signaling pathways, and we summarize the recent research efforts on these two pathways in different cancers. We also evaluate the ideal drugs that could target these two signaling pathways for cancer therapy, summarize alterations in the Notch and Wnt signaling pathways in cancer, and discuss potential signaling inhibitors as effective drugs for cancer therapy.
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Affiliation(s)
- Yu-Feng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Xin Yong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Yong Qin
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Jian-Wei Zhang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Dan Zhang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Rui Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
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23
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Lin M, Yuan YY, Liu SP, Shi JJ, Long XA, Niu LZ, Chen JB, Li Q, Xu KC. Prospective study of the safety and efficacy of a pancreatic cancer stem cell vaccine. J Cancer Res Clin Oncol 2015; 141:1827-33. [PMID: 25860618 DOI: 10.1007/s00432-015-1968-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 03/31/2015] [Indexed: 12/24/2022]
Abstract
INTRODUCTION In this trial, we isolated and cultured pancreatic cancer stem cells (CSCs) to produce a vaccine and prospectively evaluated its safety and efficacy in low-, medium-, and high-dose groups. MATERIAL AND METHODS Between February and October 2014, we enrolled 90 patients who met the enrollment criteria and assigned them to three groups (n = 30). CSC-specific and CSC-non-specific immunity pre- and post-vaccination were compared by Dunnett's multiple comparison test (one-way ANOVA). The data are presented as the mean±standard deviation. Local and systemic adverse events were recorded in the nursing records and compared using the Chi-square test. All statistical analyses were conducted using GraphPad software (GraphPad, San Diego, CA, USA). RESULTS Throughout the trial, an injection site reaction was the most common reaction (54 %), and fever was least common (9 %). The incidence of these side effects did not vary among the three groups. When the pre- and post-vaccination immunity was compared, we found that both CSC-nonspecific and CSC-specific responses were significantly increased in the high-dose group. CONCLUSION This study is the first clinical trial of a pancreatic CSC vaccine and preliminarily proves its safety and efficacy.
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Affiliation(s)
- Mao Lin
- Fuda Cancer Hospital, Jinan University School of Medicine, Guangzhou, 510665, China
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24
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Li LC, Wang DL, Wu YZ, Nian WQ, Wu ZJ, Li Y, Ma HW, Shao JH. Gastric tumor-initiating CD44 + cells and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. Oncol Lett 2015; 10:3293-3299. [PMID: 26722328 DOI: 10.3892/ol.2015.3727] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 08/17/2015] [Indexed: 12/15/2022] Open
Abstract
It has been proposed that the Notch signaling pathway may serve a pivotal role in cellular differentiation, proliferation and apoptosis. However, the function of Notch signaling in gastric cancer stem cells (GCSCs) is largely unknown. The present study aimed to delineate the role of the Notch1 pathway in GCSCs and during epithelial-mesenchymal transition (EMT). Flow cytometry was used to isolate CD44+ cells from the human gastric cancer cell line, MKN45. CD44+ cells displayed the characteristics of CSCs and exhibited higher Notch1 expression compared with CD44- cells. To investigate the role of the Notch1 pathway in GCSCs, CD44+ cells were treated with the γ-secretase inhibitor DAPT. DAPT treatment inhibited the expression of the Notch1 downstream target Hes1 and EMT markers, suppressed the properties of CSCs and impaired the invasion and proliferation capabilities of CD44+ cells. In addition, intraperitoneal treatment with DAPT effectively inhibited the growth of CD44+ cell xenograft tumors. The present study indicated that CD44+ GCSCs possess the characteristics of CSCs and that the Notch1 pathway serves a critical role in the maintenance of CSCs and EMT.
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Affiliation(s)
- Lu-Chun Li
- Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Dong-Lin Wang
- Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Yong-Zhong Wu
- Department of Radiotherapy, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Wei-Qi Nian
- Department of Galactophore, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Zhi-Juan Wu
- Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Yan Li
- Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Hui-Wen Ma
- Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China
| | - Jiang-He Shao
- Department of Oncology, Chongqing Cancer Institute, Chongqing 400030, P.R. China
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25
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Hu Y, Su H, Li X, Guo G, Cheng L, Qin R, Qing G, Liu H. The NOTCH ligand JAGGED2 promotes pancreatic cancer metastasis independent of NOTCH signaling activation. Mol Cancer Ther 2014; 14:289-97. [PMID: 25351917 DOI: 10.1158/1535-7163.mct-14-0501] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a high rate of metastasis. Numerous signaling events have been implicated in the molecular pathogenesis of this neoplasm. Aberrantly high expression of JAGGED2, one of the NOTCH ligands, often occurs in human PDAC. However, what role JAGGED2 plays in the disease development and whether JAGGED2 executes its function through activating NOTCH signaling remain to be determined. We report here that JAGGED2 plays a critical role in promoting PDAC metastasis in vitro and in vivo. Depletion of JAGGED2, but not its homolog JAGGED1, profoundly inhibited both migration and invasion without influencing cell proliferation. Furthermore, reconstitution of JAGGED2 expression rescued the migratory defect. Surprisingly, neither pharmacologic nor genetic inhibition of NOTCH downstream signaling resulted in obvious defect in metastasis. Instead, depletion of NOTCH1 expression per se gave rise to migratory defects similar to JAGGED2 ablation. Moreover, blockade of ligand-receptor interaction by a specific JAGGED2-Fc fusion protein dramatically inhibited PDAC cell migration, suggesting that tumor metastasis relies on physical interactions of JAGGED2-NOTCH1 but not Notch downstream signaling activation. Taken together, our data reveal a novel role of NOTCH in regulation of PDAC metastasis, and identify JAGGED2 as a critical mediator in this event. These findings also provide rationale for developing small molecules or biologic agents targeting JAGGED2 for therapeutic intervention.
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Affiliation(s)
- Yufeng Hu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Hexiu Su
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Xu Li
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Guoli Guo
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Ling Cheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Guoliang Qing
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
| | - Hudan Liu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
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Kothari AN, Mi Z, Zapf M, Kuo PC. Novel clinical therapeutics targeting the epithelial to mesenchymal transition. Clin Transl Med 2014; 3:35. [PMID: 25343018 PMCID: PMC4198571 DOI: 10.1186/s40169-014-0035-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 09/25/2014] [Indexed: 01/25/2023] Open
Abstract
The epithelial to mesenchymal transition (EMT) is implicated in many processes, ranging from tissue and organogenesis to cancer and metastatic spread. Understanding the key regulatory mechanisms and mediators within this process offers the opportunity to develop novel therapeutics with broad clinical applicability. To date, several components of EMT already are targeted using pharmacologic agents in fibrosis and cancer. As our knowledge of EMT continues to grow, the potential for novel therapeutics will also increase. This review focuses on the role of EMT both as a necessary part of development and a key player in disease progression, specifically the similarity in pathways used during both processes as targets for drug development. Also, the key role of the tumor microenvironment with EMT is outlined, focusing on both co-factors and cell types with the ability to modulate the progression of EMT in cancer and metastatic disease. Lastly, we discuss the current status of clinical therapies both in development and those progressed to clinical trial specifically targeting pathologic EMTs including small molecule inhibitors, non-coding RNAs, exogenous co-factors, and adjunctive therapies to current chemotherapeutics.
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Affiliation(s)
- Anai N Kothari
- Department of Surgery, Oncology Institute, Loyola University Medical Center, 2160 South First Ave, EMS Bldg, Rm 3244, Maywood 60153, IL, USA
| | - Zhiyong Mi
- Department of Surgery, Oncology Institute, Loyola University Medical Center, 2160 South First Ave, EMS Bldg, Rm 3244, Maywood 60153, IL, USA
| | - Matthew Zapf
- Department of Surgery, Oncology Institute, Loyola University Medical Center, 2160 South First Ave, EMS Bldg, Rm 3244, Maywood 60153, IL, USA
| | - Paul C Kuo
- Department of Surgery, Oncology Institute, Loyola University Medical Center, 2160 South First Ave, EMS Bldg, Rm 3244, Maywood 60153, IL, USA
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Mimeault M, Batra SK. Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Mol Aspects Med 2014; 39:3-32. [PMID: 23994756 PMCID: PMC3938987 DOI: 10.1016/j.mam.2013.08.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 08/16/2013] [Accepted: 08/21/2013] [Indexed: 12/17/2022]
Abstract
Recent studies in the field of cancer stem cells have revealed that the alterations in key gene products involved in the epithelial-mesenchymal transition (EMT) program, altered metabolic pathways such as enhanced glycolysis, lipogenesis and/or autophagy and treatment resistance may occur in cancer stem/progenitor cells and their progenies during cancer progression. Particularly, the sustained activation of diverse developmental cascades such as hedgehog, epidermal growth factor receptor (EGFR), Wnt/β-catenin, Notch, transforming growth factor-β (TGF-β)/TGF-βR receptors and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) can play critical functions for high self-renewal potential, survival, invasion and metastases of cancer stem/progenitor cells and their progenies. It has also been observed that cancer cells may be reprogrammed to re-express different pluripotency-associated stem cell-like markers such as Myc, Oct-3/4, Nanog and Sox-2 along the EMT process and under stressful and hypoxic conditions. Moreover, the enhanced expression and/or activities of some drug resistance-associated molecules such as Bcl-2, Akt/molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), hypoxia-inducible factors (HIFs), macrophage inhibitory cytokine-1 (MIC-1) and ATP-binding cassette (ABC) multidrug transporters frequently occur in cancer cells during cancer progression and metastases. These molecular events may cooperate for the survival and acquisition of a more aggressive and migratory behavior by cancer stem/progenitor cells and their progenies during cancer transition to metastatic and recurrent disease states. Of therapeutic interest, these altered gene products may also be exploited as molecular biomarkers and therapeutic targets to develop novel multitargeted strategies for improving current cancer therapies and preventing disease relapse.
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Affiliation(s)
- Murielle Mimeault
- Department of Biochemistry and Molecular Biology, College of Medicine, Fred & Pamela Buffett Cancer Center, Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, Fred & Pamela Buffett Cancer Center, Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells - what challenges do they pose? Nat Rev Drug Discov 2014; 13:497-512. [PMID: 24981363 DOI: 10.1038/nrd4253] [Citation(s) in RCA: 780] [Impact Index Per Article: 70.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.
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Affiliation(s)
- Diwakar R Pattabiraman
- Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
| | - Robert A Weinberg
- 1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA; and the MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA
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Ginnebaugh KR, Ahmad A, Sarkar FH. The therapeutic potential of targeting the epithelial-mesenchymal transition in cancer. Expert Opin Ther Targets 2014; 18:731-45. [PMID: 24758643 DOI: 10.1517/14728222.2014.909807] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The process of epithelial-to-mesenchymal transition (EMT) has long been advocated as a process during tumor progression and the acquisition of metastatic potential of human cancers. EMT has also been linked with resistance to cancer therapies. AREAS COVERED Basic research has provided evidence connecting EMT to increased invasion, angiogenesis and metastasis of cancer cells. A number of signaling pathways such as notch, wnt, hedgehog and PI3K-AKT, and various other individual factors therein, have been intricately connected to the onset of EMT. Here, we provide latest updates on the evidences that further highlight an association between various signaling pathways and EMT, with a focus on therapeutic targets that may have the potential to reverse EMT. EXPERT OPINION Our understanding of EMT and its underlying causes is rapidly evolving and a number of putative targets have been identified. It is crucial, now than ever before, to design novel translational and clinical studies for the benefit of advanced stage cancer patients with metastatic disease.
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Affiliation(s)
- Kevin R Ginnebaugh
- Karmanos Cancer Institute, Wayne State University School of Medicine, Department of Pathology , Detroit, MI 48201 , USA
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Kristoffersen K, Nedergaard MK, Villingshøj M, Borup R, Broholm H, Kjær A, Poulsen HS, Stockhausen MT. Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature. Cancer Biol Ther 2014; 15:862-77. [PMID: 24755988 DOI: 10.4161/cbt.28876] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC. METHODS Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice. RESULTS By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control. CONCLUSION Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.
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Affiliation(s)
- Karina Kristoffersen
- Department of Radiation Biology; The Finsen Center; Copenhagen University Hospital; Copenhagen, Denmark
| | - Mette Kjølhede Nedergaard
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging; Copenhagen University Hospital and University of Copenhagen; Copenhagen, Denmark
| | - Mette Villingshøj
- Department of Radiation Biology; The Finsen Center; Copenhagen University Hospital; Copenhagen, Denmark
| | - Rehannah Borup
- Center for Genomic Medicine; Copenhagen University Hospital; Copenhagen, Denmark
| | - Helle Broholm
- Department of Neuropathology; The Diagnostic Center; Copenhagen University Hospital; Copenhagen, Denmark
| | - Andreas Kjær
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging; Copenhagen University Hospital and University of Copenhagen; Copenhagen, Denmark
| | - Hans Skovgaard Poulsen
- Department of Radiation Biology; The Finsen Center; Copenhagen University Hospital; Copenhagen, Denmark
| | - Marie-Thérése Stockhausen
- Department of Radiation Biology; The Finsen Center; Copenhagen University Hospital; Copenhagen, Denmark
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Abstract
The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
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Li LC, Peng Y, Liu YM, Wang LL, Wu XL. Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. Oncol Lett 2014; 7:2160-2164. [PMID: 24932308 PMCID: PMC4049710 DOI: 10.3892/ol.2014.1980] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 02/26/2014] [Indexed: 12/13/2022] Open
Abstract
The Notch signaling pathway may be important in the development and progression of several malignancies. However, the functions of Notch signaling in epithelial-mesenchymal transition (EMT) remain largely unknown. The aim of the present study was to delineate Notch1 expression in gastric cancer (GC) and its function in GC EMT. Using quantitative polymerase chain reaction and western blot analysis, the expression of Notch1 was found to increase in GC cell lines compared with the normal gastric mucosa cell line. In addition, Notch1 expression was found to be downregulated in the non-metastatic-derived GC cell line compared with the metastatic-derived cell line. Furthermore, Notch1 expression was significantly increased in the tumor tissues compared with the adjacent normal mucosa tissues, as well as in patients with metastases than in patients without metastases. To explore the role of the Notch1 signaling pathway in EMT, the GC cell lines, AGS and MKN45, were treated with γ-secretase inhibitor DAPT. Using MTT, Transwell and clonality assays, DAPT was found to inhibit the expression of the Notch1 downstream target, Hes1, and impair the ability of the GC cell lines to migrate, invade and proliferate. The protein levels of the mesenchymal markers, vimentin, neural cadherin and Snail, were decreased; however, the expression of the epithelial marker, epithelial cadherin, was increased in the GC cell lines treated with DAPT. These results indicated that the Notch1 signaling pathway may be important in the development and progression of GC. In conclusion, DAPT inhibits the Notch1 signaling pathway, as well as the growth, invasion, metastasis and EMT of GC cells.
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Affiliation(s)
- Lu-Chun Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yang Peng
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yan-Mim Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Lu-Lu Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Xiao-Ling Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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Ma J, Xia J, Miele L, Sarkar FH, Wang Z. Notch Signaling Pathway in Pancreatic Cancer Progression. PANCREATIC DISORDERS & THERAPY 2013; 3:1000114. [PMID: 24027656 PMCID: PMC3767173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Affiliation(s)
- Jia Ma
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui, PR China
| | - Jun Xia
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui, PR China
| | - Lucio Miele
- University of Mississippi Cancer Institute, Jackson, MS 39216, USA
| | - Fazlul H Sarkar
- Department of Pathology and oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Zhiwei Wang
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui, PR China
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, MA 02215, USA
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