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1
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Shalabi S, Belayachi A, Larrivée B. Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment. Front Immunol 2024; 15:1284629. [PMID: 38375479 PMCID: PMC10875004 DOI: 10.3389/fimmu.2024.1284629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 01/09/2024] [Indexed: 02/21/2024] Open
Abstract
Emerging evidence suggests that nerves within the tumor microenvironment play a crucial role in regulating angiogenesis. Neurotransmitters and neuropeptides released by nerves can interact with nearby blood vessels and tumor cells, influencing their behavior and modulating the angiogenic response. Moreover, nerve-derived signals may activate signaling pathways that enhance the production of pro-angiogenic factors within the tumor microenvironment, further supporting blood vessel growth around tumors. The intricate network of communication between neural constituents and the vascular system accentuates the potential of therapeutically targeting neural-mediated pathways as an innovative strategy to modulate tumor angiogenesis and, consequently, neoplastic proliferation. Hereby, we review studies that evaluate the precise molecular interplay and the potential clinical ramifications of manipulating neural elements for the purpose of anti-angiogenic therapeutics within the scope of cancer treatment.
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Affiliation(s)
- Sharif Shalabi
- Maisonneuve-Rosemont Hospital Research Center, Boulevard de l’Assomption, Montréal, QC, Canada
| | - Ali Belayachi
- Maisonneuve-Rosemont Hospital Research Center, Boulevard de l’Assomption, Montréal, QC, Canada
| | - Bruno Larrivée
- Maisonneuve-Rosemont Hospital Research Center, Boulevard de l’Assomption, Montréal, QC, Canada
- Department of Biochemistry and Molecular Medicine, Montréal, QC, Canada
- Ophthalmology, Université de Montréal, boul. Édouard-Montpetit, Montréal, QC, Canada
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2
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Wu Y, Luo J, Xu B. Network Pharmacology and Bioinformatics Study of Geniposide Regulating Oxidative Stress in Colorectal Cancer. Int J Mol Sci 2023; 24:15222. [PMID: 37894904 PMCID: PMC10607277 DOI: 10.3390/ijms242015222] [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: 09/01/2023] [Revised: 10/08/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
This study aims to identify the mechanism of geniposide regulating oxidative stress in colorectal cancer (CRC) through network pharmacology and bioinformatics analysis. Targets of geniposide, oxidative stress-related targets and targets related to CRC were applied from databases. The hub genes for geniposide regulating oxidative stress in CRC were identified with the protein-protein interaction (PPI) network. Furthermore, we applied Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment to analyze the hub genes from a macro perspective. We verified the hub genes by molecular docking, GEPIA, HPA and starBase database. We identified five hub genes: IL1B, GSK3B, NOS3, RELA and CDK4. GO analysis results suggested that the anti-colorectal cancer effect of geniposide by regulating oxidative stress is possibly related to the influence of multiple biological processes, including response to temperature stimulus, response to alkaloid, nitric oxide biosynthetic process, nitric oxide metabolic process, reactive nitrogen species metabolic process, cellular response to peptide, etc. KEGG enrichment analysis results indicated that the PI3K-Akt signaling pathway, IL-17 signaling pathway, p53 signaling pathway, NF-κB signaling pathway and NOD-like receptor signaling pathway are likely to be the significant pathways. Molecular docking results showed that the geniposide had a good binding activity with the hub genes. This study demonstrates that geniposide can regulate oxidative stress in CRC, and induction of oxidative stress is one of the possible mechanisms of anti-recurrence and metastasis effects of geniposide against CRC.
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Affiliation(s)
| | | | - Baojun Xu
- Guangdong Provincial Key Laboratory IRADS, Department of Life Sciences, BNU-HKBU United International College, Zhuhai 519087, China
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3
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Papadakos SP, Stergiou IE, Gkolemi N, Arvanitakis K, Theocharis S. Unraveling the Significance of EPH/Ephrin Signaling in Liver Cancer: Insights into Tumor Progression and Therapeutic Implications. Cancers (Basel) 2023; 15:3434. [PMID: 37444544 PMCID: PMC10340246 DOI: 10.3390/cancers15133434] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Liver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic strategies. The EPH/ephrin system, which comprises a family of cell surface receptors and their corresponding ligands, has been implicated in the pathogenesis of HCC. This review paper aims to provide an overview of the current understanding of the role of the EPH/ephrin system in HCC. Specifically, we discuss the dysregulation of EPH/ephrin signaling in HCC and its impact on various cellular processes, including cell proliferation, migration, and invasion. Overall, the EPH/ephrin signaling system emerges as a compelling and multifaceted player in liver cancer biology. Elucidating its precise mechanisms and understanding its implications in disease progression and therapeutic responses may pave the way for novel targeted therapies and personalized treatment approaches for liver cancer patients. Further research is warranted to unravel the full potential of the EPH/ephrin system in liver cancer and its clinical translation.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ioanna E. Stergiou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolina Gkolemi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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4
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Chu LY, Huang BL, Huang XC, Peng YH, Xie JJ, Xu YW. EFNA1 in gastrointestinal cancer: Expression, regulation and clinical significance. World J Gastrointest Oncol 2022; 14:973-988. [PMID: 35646281 PMCID: PMC9124989 DOI: 10.4251/wjgo.v14.i5.973] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/17/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases which play an indispensable role in normal growth and development or in the pathophysiology of various tumors. The role of EFNA1 in tumorigenesis and development is complex and depends on the cell type and microenvironment which in turn affect the expression of EFNA1. This article reviews the expression, prognostic value, regulation and clinical significance of EFNA1 in gastrointestinal tumors.
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Affiliation(s)
- Ling-Yu Chu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bin-Liang Huang
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xu-Chun Huang
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Esophageal Cancer Research Institute, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Esophageal Cancer Research Institute, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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5
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Davis L, Recktenwald M, Hutt E, Fuller S, Briggs M, Goel A, Daringer N. Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy. Cancers (Basel) 2022; 14:1259. [PMID: 35267567 PMCID: PMC8909461 DOI: 10.3390/cancers14051259] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/26/2022] [Accepted: 02/26/2022] [Indexed: 02/06/2023] Open
Abstract
Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions.
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Affiliation(s)
- Leah Davis
- Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, USA
| | - Matthias Recktenwald
- Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, USA
| | - Evan Hutt
- Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, USA
| | - Schuyler Fuller
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Madison Briggs
- Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, USA
| | - Arnav Goel
- Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, USA
| | - Nichole Daringer
- Department of Biomedical Engineering, Rowan University, 201 Mullica Hill Rd, Glassboro, NJ 08028, USA
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6
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Zou D, Song J, Deng M, Ma Y, Yang C, Liu J, Wang S, Wen Z, Tang Y, Qu X, Zhang Y. Bufalin inhibits peritoneal dissemination of gastric cancer through endothelial nitric oxide synthase-mitogen-activated protein kinases signaling pathway. FASEB J 2021; 35:e21601. [PMID: 33913201 DOI: 10.1096/fj.202002780r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/19/2021] [Accepted: 04/01/2021] [Indexed: 01/11/2023]
Abstract
Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC-803 and high-potential peritoneal dissemination cell line MKN-45P were treated with bufalin or L-NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3-MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD.
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Affiliation(s)
- Dan Zou
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Jincheng Song
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China.,Department of Oncology, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Mingming Deng
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yanju Ma
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Chunjiao Yang
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Jiaqing Liu
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Song Wang
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Zhenpeng Wen
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
| | - Yu Tang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, the First Hospital of China Medical University, Shenyang, China
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7
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Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation. Nat Commun 2021; 12:2788. [PMID: 33986289 PMCID: PMC8119676 DOI: 10.1038/s41467-021-23075-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 04/09/2021] [Indexed: 12/12/2022] Open
Abstract
Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.
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8
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Zou D, Li Z, Lv F, Yang Y, Yang C, Song J, Chen Y, Jin Z, Zhou J, Jiang Y, Ma Y, Jing Z, Tang Y, Zhang Y. Pan-Cancer Analysis of NOS3 Identifies Its Expression and Clinical Relevance in Gastric Cancer. Front Oncol 2021; 11:592761. [PMID: 33747912 PMCID: PMC7969995 DOI: 10.3389/fonc.2021.592761] [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: 12/10/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background:NOS3 (endothelial NOS, eNOS) is a member of the nitric oxide synthase (NOS) enzyme family, mainly participating in nitric oxide (NO) generation. NOS3 has been reported to inhibit apoptosis and promote angiogenesis, proliferation, and invasiveness. However, the expression pattern of NOS3 and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective. Methods: Data from the Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and the Cancer Therapeutics Response Portal (CTRP) were employed and NOS3 expression was comprehensively analyzed in normal tissues, cancer tissues, and cell lines. Immunohistochemical staining of tissue sections were used to validate the prognostic role of NOS3 in gastric cancer patients. GSVA and GSEA analyses were performed to investigate signaling pathways related to NOS3 expression. Results: In normal tissues, NOS3 was expressed highest in the spleen and lowest in the blood. NOS3 expression was increased in stomach adenocarcinoma (STAD) and significantly associated with poor prognosis of patients. Immunohistochemical staining validated that NOS3 was an independent prognostic factor of gastric cancer. Several canonical cancer-related pathways were found to be correlated with NOS3 expression in STAD. The expression of NOS3 was related to the response to QS-11 and brivinib in STAD. Conclusions:NOS3 was an independent prognostic factor for patients with STAD. Increased expression of NOS3 influenced occurrence and development of STAD through several canonical cancer-related pathways. Drug response analysis reported drugs to suppress NOS3. NOS3 might be a novel target for gastric cancer treatment.
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Affiliation(s)
- Dan Zou
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
| | - Fei Lv
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yi Yang
- Laboratory Animal Center, China Medical University, Shenyang, China
| | - Chunjiao Yang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Jincheng Song
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China.,Lymphoma and Myeloma Diagnosis and Treatment Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yang Chen
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, China
| | - Zi Jin
- The First Department of Oncology, Shenyang Fifth People's Hospital, Shenyang, China
| | - Jinpeng Zhou
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Yang Jiang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.,Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanju Ma
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Zhitao Jing
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Yu Tang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
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9
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Endothelial Cells as Tools to Model Tissue Microenvironment in Hypoxia-Dependent Pathologies. Int J Mol Sci 2021; 22:ijms22020520. [PMID: 33430201 PMCID: PMC7825710 DOI: 10.3390/ijms22020520] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/27/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Endothelial cells (ECs) lining the blood vessels are important players in many biological phenomena but are crucial in hypoxia-dependent diseases where their deregulation contributes to pathology. On the other hand, processes mediated by ECs, such as angiogenesis, vessel permeability, interactions with cells and factors circulating in the blood, maintain homeostasis of the organism. Understanding the diversity and heterogeneity of ECs in different tissues and during various biological processes is crucial in biomedical research to properly develop our knowledge on many diseases, including cancer. Here, we review the most important aspects related to ECs’ heterogeneity and list the available in vitro tools to study different angiogenesis-related pathologies. We focus on the relationship between functions of ECs and their organo-specificity but also point to how the microenvironment, mainly hypoxia, shapes their activity. We believe that taking into account the specific features of ECs that are relevant to the object of the study (organ or disease state), especially in a simplified in vitro setting, is important to truly depict the biology of endothelium and its consequences. This is possible in many instances with the use of proper in vitro tools as alternative methods to animal testing.
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10
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Hao Y, Li G. Role of EFNA1 in tumorigenesis and prospects for cancer therapy. Biomed Pharmacother 2020; 130:110567. [PMID: 32745910 DOI: 10.1016/j.biopha.2020.110567] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/14/2020] [Accepted: 07/26/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the major threats to human health. It is of vital importance to reveal the mechanisms of tumorigenesis, identify effective biomarkers and develop novel treatments to improve patient outcome. EFNA1 (ephrinA1) is a member of the EFN family, and it has been studied extensively since its discovery in 1990. Increasing evidence indicates that EFNA1 plays a pivotal role in the pathogenesis of tumors. We provide a detailed overview of the expression and prognostic value of EFNA1 in different types of human malignancies. We briefly discuss the mechanisms of EFNA1 induction in hypoxic environments and its pro-angiogenic function in different cancer cells. We describe the effects of EFNA1 on tumor growth, invasiveness and metastasis. We summarize recent advances in EFNA1-associated cancer therapeutics with emphasis on the prospect of novel anti-tumor methods based on EFNA1.
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Affiliation(s)
- Yongping Hao
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Liaoning, 110001, China.
| | - Guang Li
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Liaoning, 110001, China.
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11
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Wechman SL, Emdad L, Sarkar D, Das SK, Fisher PB. Vascular mimicry: Triggers, molecular interactions and in vivo models. Adv Cancer Res 2020; 148:27-67. [PMID: 32723566 DOI: 10.1016/bs.acr.2020.06.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Vascular mimicry is induced by a wide array of genes with functions related to cancer stemness, hypoxia, angiogenesis and autophagy. Vascular mimicry competent (VM-competent) cells that form de novo blood vessels are common in solid tumors facilitating tumor cell survival and metastasis. VM-competent cells display increased levels of vascular mimicry selecting for stem-like cells in an O2-gradient-dependent manner in deeply hypoxic tumor regions, while also aiding in maintaining tumor cell metabolism and stemness. Three of the principal drivers of vascular mimicry are EphA2, Nodal and HIF-1α, however, directly or indirectly many of these molecules affect VE-Cadherin (VE-Cad), which forms gap-junctions to bind angiogenic blood vessels together. During vascular mimicry, the endothelial-like functions of VM-competent cancer stem cells co-opt VE-Cad to bind cancer cells together to create cancer cell-derived blood conducting vessels. This process potentially compensates for the lack of access to blood and nutrient in avascular tumors, simultaneously providing nutrients and enhancing cancer invasion and metastasis. Current evidence also supports that vascular mimicry promotes cancer malignancy and metastasis due to the cooperation of oncogenic signaling molecules driving cancer stemness and autophagy. While a number of currently used cancer therapeutics are effective inhibitors of vascular mimicry, developing a new class of vascular mimicry specific inhibitors could allow for the treatment of angiogenesis-resistant tumors, inhibit cancer metastasis and improve patient survival. In this review, we describe the principal vascular mimicry pathways in addition to emphasizing the roles of hypoxia, autophagy and select proangiogenic oncogenes in this process.
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Affiliation(s)
- Stephen L Wechman
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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12
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Casadei-Gardini A, Vagheggini A, Gelsomino F, Spallanzani A, Ulivi P, Orsi G, Rovesti G, Andrikou K, Tamburini E, Scartozzi M, Cascinu S. Is There an Optimal Choice in Refractory Colorectal Cancer? A Network Meta-Analysis. Clin Colorectal Cancer 2020; 19:82-90.e9. [PMID: 32192883 DOI: 10.1016/j.clcc.2019.10.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 10/08/2019] [Accepted: 10/08/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND In the absence of head-to-head comparison studies, the present network meta-analysis evaluated and compared the efficacy of 4 therapeutic alternatives for refractory colorectal cancer. MATERIALS AND METHODS The search focused on results from phase III randomized controlled trials. Separate (subgroup) network meta-analyses were conducted to obtain drug comparisons stratified by various patient characteristics. The principal outcome of interest was overall survival (OS). RESULTS No difference in OS was found between regorafenib and TAS-102. For a rectal primary location, TAS-102 conferred benefit versus placebo (hazard ratio [HR], 0.671), but regorafenib did not (HR, 0.950). For patients aged > 65 years, TAS-102 showed benefit versus placebo (HR, 0.579) but regorafenib did not (HR, 0.816). For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 in the indirect comparison, regorafenib showed benefit versus placebo (HR, 0.687), as did TAS-102 (HR, 0.756) but with a lower advantage. For patients with RAS wild type not previously treated with anti-EGFR antibodies, panitumumab was the optimal choice for OS. CONCLUSIONS No differences in OS were found between regorafenib and TAS-102. Possible greater efficacy was found for TAS-102 compared with regorafenib for patients with a rectal primary location, ECOG PS > 0, and age > 65 years. In contrast, regorafenib showed possible greater effectiveness for patients with ECOG PS 0 and age < 65 years. In the RAS WT population, the anti-EGFR drug showed superiority with respect to TAS-102 and regorafenib. These results should be viewed as only exploratory, and further prospective studies are warranted to validate these data.
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Affiliation(s)
- Andrea Casadei-Gardini
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy.
| | - Alessandro Vagheggini
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
| | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy
| | - Giulia Orsi
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
| | - Giulia Rovesti
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
| | - Kalliopi Andrikou
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
| | - Emiliano Tamburini
- Department of Medical Oncology, Cardinale Giovanni Panico Hospital of Tricase, Tricase, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, "Duilio Casula" Polyclinic, Cagliari State University, Cagliari, Italy
| | - Stefano Cascinu
- Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
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13
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Guo F, Yuan Y. Tumor Necrosis Factor Alpha-Induced Proteins in Malignant Tumors: Progress and Prospects. Onco Targets Ther 2020; 13:3303-3318. [PMID: 32368089 PMCID: PMC7182456 DOI: 10.2147/ott.s241344] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/04/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor necrosis factor (TNF) is the first cytokine used in tumor biotherapy, but TNF-related drugs are limited by the lack of specific targets. Tumor necrosis factor alpha-induced proteins (TNFAIPs), derived from TNF, is a protein family and participates in proliferation, invasion and metastasis of tumor cells. In order to better understand biological functions and potential roles of TNFAIPs in malignant tumors, this paper in the form of “Gene–Protein–Tumor correlation” summarizes the biological characteristics, physiological functions and mechanisms of TNFAIPs by searching National Center of Biotechnology Information, GeneCards, UniProt and STRING databases. The relationship between TNFAIPs and malignant tumors is analyzed, and protein–protein interaction diagram in members of TNFAIPs is drawn based on TNF for the first time. We find that TNF as a key factor is related to TNFAIP1, TNFAIP3, TNFAIP5, TNFAIP6, TNFAIP8 and TNFAIP9, which can be directly involved in activating TNFAIP1, TNFAIP5, TNFAIP8 and TNFAIP9. We confirm that the mechanism of TNFAIP1, TNFAIP2 and TNFAIP3 inducing tumors may be related to NF-κB signaling pathway, but the mechanism of tumor induction by other members of TNFAIPs is not clear. In the future, translational studies are needed to explore the mechanisms of TNF-TNFAIPs-tumors.
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Affiliation(s)
- Fang Guo
- Liaoning Provincial Education Department, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang City, Liaoning Province, People's Republic of China.,Department of Oncology, PLA Cancer Center, General Hospital of Northern Theater Command, Shenyang City, Liaoning Province, People's Republic of China
| | - Yuan Yuan
- Liaoning Provincial Education Department, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang City, Liaoning Province, People's Republic of China
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14
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Ma TT, Wang L, Wang JL, Liu YJ, Chen YC, He HJ, Song Y. Hypoxia-Induced Cleavage Of Soluble ephrinA1 From Cancer Cells Is Mediated By MMP-2 And Associates With Angiogenesis In Oral Squamous Cell Carcinoma. Onco Targets Ther 2019; 12:8491-8499. [PMID: 31686863 PMCID: PMC6799903 DOI: 10.2147/ott.s213252] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 09/18/2019] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION ephrinA1 plays important roles in tumor angiogenesis. Matrix metalloproteases (MMPs) can cleave ephrinA1 from the cell membrane into extracellular environment. However, how soluble ephrinA1 is modulated by hypoxia and whether MMPs participate in this hypoxic process remains to be investigated in detail. METHODS Thirty-seven patients with oral squamous cell carcinoma (OSCC) were included in the present study for HIF-1α, MMP-2, MMP-9 and ephrinA1 detection by immunohistochemistry. Serum samples from 35 patients were collected both preoperatively and postoperatively to confirm the existence of soluble ephrinA1 by ELISA. Block assay and Western blot analysis were further carried out to elucidate the proteolysis mechanism of ephrinA1 under hypoxic condition in vitro. RESULTS Our data demonstrated that HIF-1α, MMP-2, MMP-9 and ephrinA1 expressed positively, and correlated with microvessel density in OSCCs, except for MMP-9. The serum expression level of ephrinA1 in OSCC patients decreased significantly after surgical removal of the solid tumors. In vitro experiments indicated that GM6001, a MMP-specific inhibitor, could reduce hypoxia-induced soluble ephrinA1 secretion from SCC cells. Further Western blot analysis confirmed that both HIF-1α and MMP-2 were up-regulated by hypoxia in a similar time-dependent manner, with the MMP-9 expression unchanged during this course. CONCLUSION These results suggested a possible novel mechanism that ephrinA1 secretion is mediated by HIF-1α/MMP-2 signaling cascade which may play pivotal roles in OSCC neovascularization in a paracrine manner.
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Affiliation(s)
- Ting-Ting Ma
- Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China
| | - Lin Wang
- Department of Oral and Maxillofacial-Head and Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, People’s Republic of China
| | - Jun-Lin Wang
- Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China
| | - Yan-Jie Liu
- Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China
| | - Yu-Cong Chen
- Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China
| | - Hu-Jie He
- Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China
| | - Yong Song
- Department of Stomatology, Liuzhou People’s Hospital, Guangxi, People’s Republic of China
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15
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Casadei-Gardini A, Scarpi E, Ulivi P, Palladino MA, Accettura C, Bernardini I, Spallanzani A, Gelsomino F, Corbelli J, Marisi G, Ruscelli S, Valgiusti M, Frassineti GL, Passardi A. Prognostic role of a new inflammatory index with neutrophil-to-lymphocyte ratio and lactate dehydrogenase (CII: Colon Inflammatory Index) in patients with metastatic colorectal cancer: results from the randomized Italian Trial in Advanced Colorectal Cancer (ITACa) study. Cancer Manag Res 2019; 11:4357-4369. [PMID: 31191000 PMCID: PMC6522652 DOI: 10.2147/cmar.s198651] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/27/2019] [Indexed: 12/25/2022] Open
Abstract
Aim: The aim of this study was to investigate the role of a new inflammatory index (Colon Inflammatory Index [CII]) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT)+ bevacizumab or CT alone. Patients and methods: Between November 14, 2007 and March 6, 2012, 276 patients diagnosed with CRC were available for baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH). We divided the population into three groups on basis of the CII index. Results: At baseline in all populations, median PFS and OS was predictive of clinical outcome (p<0.0001). Following adjustment for clinical covariates, multivariate analysis confirmed CII index as an independent prognostic factor. The CII index was also predictive when we evaluated the two distinct arms with (p=0.0009) or without bevacizumab (p=0.0001). When we divided right side versus left side for treatment regimen (CT plus bevacizumab versus only bevacizumab), we found a benefit of bevacizumab versus only CT in the right side in patients treated with bevacizumab and not in patients treated with only chemotherapy. Conversely, we found no difference the left side, but we found a difference in the poor group of 4 months in favor to only chemotherapy. Conclusion: Our results indicate that the CII index is a good prognostic marker for mCRC patients in first line treatment with CT with or without bevacizumab. Trial registration: NCT01878422 ClinicalTrials.gov; date of registration: June 7, 2013.
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Affiliation(s)
- Andrea Casadei-Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, IRST IRCCS, Meldola, Italy
| | | | | | | | - Andrea Spallanzani
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | | | | | - Silvia Ruscelli
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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16
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Wijeratne D, Rodger J, Stevenson A, Wallace H, Prêle CM, Wood FM, Fear MW. Ephrin-A2 affects wound healing and scarring in a murine model of excisional injury. Burns 2018; 45:682-690. [PMID: 30482614 DOI: 10.1016/j.burns.2018.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/14/2018] [Accepted: 10/04/2018] [Indexed: 12/18/2022]
Abstract
Ephrin ligand/Eph receptor signaling is important in both tissue development and homeostasis. There is increasing evidence that Ephrin/Eph signaling is important in the skin, involved in hair follicle cycling, epidermal differentiation, cutaneous innervation and skin cancer. However, there is currently limited information on the role of Ephrin/Eph signaling in cutaneous wound healing. Here we report the effects of the Ephrin-A2 and A5 ligands on wound healing. Using Ephrin-A2-/-, Ephrin-A5-/- and Ephrin-A2A5-/- transgenic mice, in vitro wound healing assays were conducted using isolated keratinocytes and fibroblasts. Ephrin-A2-/-, Ephrin-A2A5-/- and wild type mice with excisional wounds were used to analyze the impact of these ligands on wound closure, scar outcome, collagen orientation and re-innervation in vivo. The absence of the Ephrin-A2 and A5 ligands did not have any effect on dermal fibroblast proliferation or on fibroblast or keratinocyte migration. The loss of Ephrin-A2 and A5 ligands did not impact on the rate of wound closure or re-innervation after injury. However, changes in the gross morphology of the healed scar and in collagen histology of the scar dermis were observed in transgenic mice. Therefore Ephrin-A2 and A5 ligands may play an important role in final scar appearance associated with collagen deposition and structure.
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Affiliation(s)
- Dulharie Wijeratne
- Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Australia
| | - Jennifer Rodger
- Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Australia
| | - Andrew Stevenson
- Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Australia
| | - Hilary Wallace
- Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Australia
| | - Cecilia M Prêle
- The Institute for Respiratory Health, The University of Western Australia, Nedlands, Western Australia, Australia; Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Fiona M Wood
- Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Australia; Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia; The Fiona Wood Foundation, Perth, Western Australia, Australia; Burns Service of Western Australia, WA Department of Health, Perth, Western Australia, Australia
| | - Mark W Fear
- Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Australia; The Institute for Respiratory Health, The University of Western Australia, Nedlands, Western Australia, Australia; The Fiona Wood Foundation, Perth, Western Australia, Australia.
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17
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Suksawat M, Techasen A, Namwat N, Boonsong T, Titapun A, Ungarreevittaya P, Yongvanit P, Loilome W. Inhibition of endothelial nitric oxide synthase in cholangiocarcinoma cell lines - a new strategy for therapy. FEBS Open Bio 2018; 8:513-522. [PMID: 29632805 PMCID: PMC5881549 DOI: 10.1002/2211-5463.12388] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 12/14/2017] [Accepted: 01/01/2018] [Indexed: 12/18/2022] Open
Abstract
The isoform of nitric oxide synthase (NOS) found in endothelial cells (eNOS) plays a crucial role in vasodilation. We recently reported the activation of eNOS in cholangiocarcinoma (CCA) tissues and cell lines. Moreover, we also reported that the abundance of eNOS and phosphorylated eNOS (p-eNOS), as well as its upstream regulator proteins, is significantly associated with the metastatic status of CCA patients. However, the function of eNOS in CCA progression has not been addressed. Therefore, the present study aimed to investigate the function of eNOS involved in the migration and invasion ability of CCA cell lines. The results reveal that eNOS activation significantly increases migration and invasion ability of CCA cells via the up-regulation of phosphorylated vasodilator-stimulated protein (p-VASP). A combination treatment with recombinant human vascular endothelial growth factor C and eNOS inhibitor (Nω-nitro-l-arginine methyl ester hydrochloride) resulted in the down-regulation of p-VASP, as well as a decreased migration and invasion ability of the CCA cell line. Thus, this work suggests that eNOS can serve as an attractive target to inhibit the progression of CCA.
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Affiliation(s)
- Manida Suksawat
- Department of Biochemistry Faculty of Medicine Khon Kaen University Thailand.,Cholangiocarcinoma Research Institute Khon Kaen University Thailand
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute Khon Kaen University Thailand.,Faculty of Associated Medical Science Khon Kaen University Thailand.,Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand
| | - Nisana Namwat
- Department of Biochemistry Faculty of Medicine Khon Kaen University Thailand.,Cholangiocarcinoma Research Institute Khon Kaen University Thailand.,Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand
| | - Thianrut Boonsong
- Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand.,Department of Surgery Faculty of Medicine Khon Kaen University Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute Khon Kaen University Thailand.,Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand.,Department of Surgery Faculty of Medicine Khon Kaen University Thailand
| | - Piti Ungarreevittaya
- Cholangiocarcinoma Research Institute Khon Kaen University Thailand.,Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand.,Department of Pathology Faculty of Medicine Khon Kaen University Thailand
| | - Puangrat Yongvanit
- Cholangiocarcinoma Research Institute Khon Kaen University Thailand.,Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand
| | - Watcharin Loilome
- Department of Biochemistry Faculty of Medicine Khon Kaen University Thailand.,Cholangiocarcinoma Research Institute Khon Kaen University Thailand.,Cholangiocarcinoma Screening and Care Program (CASCAP) Khon Kaen University Thailand
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18
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Involvement of the Urokinase Receptor and Its Endogenous Ligands in the Development of the Brain and the Formation of Cognitive Functions. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11055-017-0525-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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19
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Suksawat M, Techasen A, Namwat N, Yongvanit P, Khuntikeo N, Titapun A, Koonmee S, Loilome W. Upregulation of endothelial nitric oxide synthase (eNOS) and its upstream regulators in Opisthorchis viverrini associated cholangiocarcinoma and its clinical significance. Parasitol Int 2017; 66:486-493. [DOI: 10.1016/j.parint.2016.04.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 04/04/2016] [Accepted: 04/29/2016] [Indexed: 12/16/2022]
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20
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Zhou L, Chen H, Mao X, Qi H, Baker PN, Zhang H. G-protein-coupled receptor 30 mediates the effects of estrogen on endothelial cell tube formation in vitro. Int J Mol Med 2017; 39:1461-1467. [PMID: 28440394 PMCID: PMC5428938 DOI: 10.3892/ijmm.2017.2957] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 04/04/2017] [Indexed: 11/05/2022] Open
Abstract
The placenta is the exchange organ between the mother and the fetus. The inadequate function of this organ is associated with a number of pregnancy disorders. Hypoxia and oxidative stress during placental development may induce endothelial dysfunction, resulting in the reduction in the perfusion of the placenta. During pregnancy, the levels of estrogen are increased. Decreased estrogen levels have been reported in women with preeclampsia. However, whether estrogen is involved in placental angiogenesis remains unclear. In this study, we aimed to investigate the effects of estrogen on endothelial cell tube formation and to elucidate the underlying mechanisms. For this purpose, human umbilical vein endothelial cells (HUVECs) were cultured with 17‑β‑estradiol under conditions of hypoxia/reoxygenation (H/R). The total pipe length of the tube‑like structure on endothelial cells was measured. The expression levels of G‑protein‑coupled receptor 30 (GPR30) and endothelial nitric oxide synthase (eNOS) and Akt were also measured in the endothelial cells following treatment with 17‑β‑estradiol under H/R conditions by western blot analysis and immunostaining. We found that the total pipe length of the tube‑like structure on endothelial cells was significantly reduced. This reduction was reversed by treatment with 17‑β‑estradiol. The expression of GPR30 in endothelial cells was significantly increased following treatment with 17‑β‑estradiol under H/R conditions. Furthermore, the levels of eNOS and Akt in endothelial cells were also significantly increased following treatment with 17-β-estradiol under H/R conditions. The activation of eNOS was inhibited by wortmannin, an inhibitor of PI3K/Akt. Our data thus demonstrate that estrogen prevents the failure of endothelial cell tube formation induced by H/R. GPR30 plays an important role in these protective effects through the activation of eNOS and Akt in endothelial cells. Our data suggest that increased levels of estrogen are important for placental angiogenesis.
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Affiliation(s)
- Liyuan Zhou
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hong Chen
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xun Mao
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hongbo Qi
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Philip N Baker
- Canada‑China‑New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hua Zhang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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21
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Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling. Int J Mol Sci 2017; 18:ijms18030524. [PMID: 28257034 PMCID: PMC5372540 DOI: 10.3390/ijms18030524] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 02/14/2017] [Accepted: 02/22/2017] [Indexed: 02/07/2023] Open
Abstract
Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 μg). Cisplatin toxicity (IC50, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 μg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway.
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22
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Mammadzada P, Gudmundsson J, Kvanta A, André H. Differential hypoxic response of human choroidal and retinal endothelial cells proposes tissue heterogeneity of ocular angiogenesis. Acta Ophthalmol 2016; 94:805-814. [PMID: 27255568 DOI: 10.1111/aos.13119] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 04/14/2016] [Indexed: 02/06/2023]
Abstract
PURPOSE To elaborate molecular differences between choroidal and retinal angiogenesis by generating and comparatively analysing human primary choroidal and retinal endothelial cell (CEC and REC) lines. METHODS Human CEC and REC were isolated by positive selection and were cultured. Characterization was performed by immunostaining for endothelial cell (EC)-specific markers. Total RNA and protein were extracted from normoxic or hypoxic CEC and REC cultures. Quantitative polymerase chain reaction (PCR) arrays were used to comparatively analyse 133 genes between CEC and REC, and the expression differences were calculated by ΔΔCt method. A total of 57 angiogenesis-related protein expression differences were investigated by Western blot and proteome profiler and were calculated by densitometry. RESULTS Primary human CEC and REC lines stained positively for all EC markers and demonstrated high purity with similar staining and morphology. Under normoxia, CEC showed significantly lower expression levels for cell proliferation and vessel maturation genes and higher expression levels for inflammation-related genes when compared to REC. In response to hypoxia, CEC and REC displayed differential regulation for a multitude of angiogenesis-related genes and proteins. Furthermore, within the vascular endothelial growth factor (VEGF) family, CEC showed preferential upregulation for vascular endothelial growth factor A (VEGFA) while REC upregulated placenta growth factor (PlGF) levels. CONCLUSION Differential normoxic and hypoxic regulation of angiogenesis-related factors by CEC and REC outlines tissue heterogeneity of ocular angiogenesis and suggests that tissue specificity should be considered as a novel treatment modality for successfully overcoming choroidal and retinal angiogenic conditions in the clinic.
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Affiliation(s)
- Parviz Mammadzada
- Section of Ophthalmology and Vision; Department of Clinical Neuroscience; St. Erik Eye Hospital; Karolinska Institute; Stockholm Sweden
| | - Johann Gudmundsson
- Section of Ophthalmology and Vision; Department of Clinical Neuroscience; St. Erik Eye Hospital; Karolinska Institute; Stockholm Sweden
| | - Anders Kvanta
- Section of Ophthalmology and Vision; Department of Clinical Neuroscience; St. Erik Eye Hospital; Karolinska Institute; Stockholm Sweden
| | - Helder André
- Section of Ophthalmology and Vision; Department of Clinical Neuroscience; St. Erik Eye Hospital; Karolinska Institute; Stockholm Sweden
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23
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Jiang YH, Sun W, Li W, Hu HZ, Zhou L, Jiang HH, Xu JX. Calycosin-7-O-β-D-glucoside promotes oxidative stress-induced cytoskeleton reorganization through integrin-linked kinase signaling pathway in vascular endothelial cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 15:315. [PMID: 26346982 PMCID: PMC4562353 DOI: 10.1186/s12906-015-0839-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Accepted: 08/28/2015] [Indexed: 02/06/2023]
Abstract
Background Dysfunction of vascular endothelium is implicated in many pathological situations. Cytoskeleton plays an importance role in vascular endothelial permeability barrier and inflammatory response. Many Chinese herbs have the endothelial protective effect, of which, “Astragalus membranaceus” is a highly valued herb for treatment of cardiovascular and renal diseases in traditional Chinese medicine, In this study, we tested whether calycosin-7-O-β-D-glucoside (Calycosin), a main effective monomer component of “Astragalus membranaceus”, could protect endothelial cells from bacterial endotoxin (LPS)-induced cell injury. Methods Endothelial cell injury was induced by exposing human umbilical vein endothelial cells (HUVECs) to LPS. The effects of calycosin on LPS-induced changes in cell viability, apoptosis rate, cell migration, nitric oxide synthase (NOS), generationof intracellular reactive oxygen species (ROS) and cytoskeleton organization were determined. Microarray assay was employed to screen the possible gene expression change. Based on the results of microarray assay, the expression profile of genes involved in Rho/ROCK pathway and AKT pathway were further evaluated with quantitative real-time RT-PCR or western blot methods. Results Calycosin improved cell viability, suppressed apoptosis and protected the cells from LPS-induced reduction in cell migration and generation of ROS, protein level of NOS at a comparable magnitude to that of Y27632 and valsartan. Similar to Y27632 and valsartan, Calycosin, also neutralized LPS-induced actomyosin contraction and vinculin protein aggregation. Microarray assay, real-time PCR and western blot results revealed that LPS induced expression of FN, ITG A5, RhoA, PI3K (or PIP2 in western blotting), FAK, VEGF and VEGF R2, and inhibited expression of MLCP. We believed multiple pathways involved in the regulation of calycosin on HUVECs. Calycosin are considered to be able to activate MLCP through promoting the generation of NO, decreasing PMLC, suppressing the cytoskeleton remodeling caused by activation of Rho/ROCK pathway and inhibiting AKT pathway by decreasing VEGF, VEGF R2 and PI3K level. Conclusion Calycosin protected HUVEC from LPS-induced endothelial injury, possibly through suppression of Rho/ROCK pathway and regulation of AKT pathway.
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24
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Zhu L, Dissanayaka WL, Green DW, Zhang C. Stimulation of EphB2/ephrin-B1 signalling by tumour necrosis factor alpha in human dental pulp stem cells. Cell Prolif 2015; 48:231-8. [PMID: 25643922 DOI: 10.1111/cpr.12172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 11/08/2014] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVES The aim of this study was to investigate whether in vitro stimulation of dental pulp stem cells (DPSCs) by tumour necrosis factor alpha (TNF-α) would induce secretion of EphB2/ephrin-B1 signalling. MATERIALS AND METHODS Dental pulp stem cells isolated from human dental pulp were treated with TNF-α (5-100 ng/ml) over 2-48 h. EphB2/ephrin-B1 mRNA and protein levels were measured by real-time polymerase chain reaction (RT-PCR) and western blot analysis respectively. Additionally, DPSCs were pre-incubated with TNF-α receptor neutralizing antibodies or infected with nuclear factor-kappa B (NF-ĸB) inhibitor, p38 MAPK inhibitor, Jun N-terminal kinase (JNK) inhibitor and MEK inhibitor before TNF-α treatment. Results were analysed by one-way ANOVA. RESULTS Tumour necrosis factor alpha increased EphB2 mRNA expression in DPSCs at concentrations up to 20 ng/ml and ephrin-B1 at concentrations up to 40 ng/ml (P < 0.05). Its mRNA expression reached maximum at 24 h when treated with TNF-α at 20 ng/ml (P < 0.05). EphB2/ephrin-B1 protein expression levels were high at 16 and 24 h as shown by western blotting. Neutralizing antibodies for TNFR1/2 receptors down-regulated EphB2/ephrin-B1 mRNA expression (P < 0.05) and ephrin-B1 protein expression, but not EphB2 protein expression. JNK-inhibitor inhibited EphB2 mRNA expression only (P < 0.05). CONCLUSIONS EphB2/ephrin-B1 were invoked in DPSCs with TNF-α treatment via the JNK-dependent pathway, but not NF-ĸB, p38 MAPK or MEK signalling.
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Affiliation(s)
- Lifang Zhu
- Comprehensive Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
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Zhao C, Yan W, Zu X, Chen M, Liu L, Zhao S, Liu H, Hu X, Luo R, Xia Y, Qi L. Association between endothelial nitric oxide synthase 894G>T polymorphism and prostate cancer risk: a meta-analysis of literature studies. Tumour Biol 2014; 35:11727-33. [PMID: 25374059 DOI: 10.1007/s13277-014-2097-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 05/13/2014] [Indexed: 01/28/2023] Open
Abstract
To date, several studies have been conducted to assess the association between endothelial nitric oxide synthase (eNOS) gene 894G > T polymorphism and prostate cancer (PCa) risk, but the results are conflicting. To derive a more precise estimation of the relationship between 894G > T polymorphism and PCa risk, the present meta-analysis was performed. A total of eight case-control studies were included in this meta-analysis. The pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to evaluate the associations. Our results suggested that 894G > T polymorphism is associated with PCa risk under codominant (GT vs. GG) (OR = 1.11, 95 % CI = 1.01-1.22, P = 0.04) and overdominant (GT vs. GG + TT) (OR = 1.12, 95 % CI = 1.02-1.23, P = 0.02) models in the overall population, while there are no associations observed under dominant (GT + TT vs. GG), recessive (TT vs. GG + GT), and allelic (T vs. G) models. Moreover, when the eligible studies were stratified according to sources of control, significant association between 894G > T polymorphism and susceptibility of PCa was also identified under codominant (OR = 1.12, 95 % CI = 1.01-1.24, P = 0.03) and overdominant (OR = 1.13, 95 % CI = 1.02-1.25, P = 0.02) models when using healthy individuals as control. However, there are no significant associations found under any genetic models when using BPH patients as control group. In conclusion, the present meta-analysis suggested that the eNOS gene 894G > T polymorphism might be a risk factor in the onset of PCa.
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Affiliation(s)
- Cheng Zhao
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, Changsha, Hunan, People's Republic of China,
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