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Igbo BT, Jentsch C, Linge A, Plesca I, Kuzay Y, Löck S, Kumaravadivel MS, Doms S, Stolz-Kieslich L, Pollack D, Brückmann S, Tittlbach H, Weitz J, Aust D, Apolle R, Schmitz M, Troost EGC. Correlation of microscopic tumor extension with tumor microenvironment in esophageal cancer patients. Strahlenther Onkol 2024; 200:595-604. [PMID: 38727811 PMCID: PMC11186916 DOI: 10.1007/s00066-024-02234-6] [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: 12/10/2023] [Accepted: 03/17/2024] [Indexed: 06/21/2024]
Abstract
OBJECTIVE In the era of image-guided adaptive radiotherapy, definition of the clinical target volume (CTV) is a challenge in various solid tumors, including esophageal cancer (EC). Many tumor microenvironmental factors, e.g., tumor cell proliferation or cancer stem cells, are hypothesized to be involved in microscopic tumor extension (MTE). Therefore, this study assessed the expression of FAK, ILK, CD44, HIF-1α, and Ki67 in EC patients after neoadjuvant radiochemotherapy followed by tumor resection (NRCHT+R) and correlated these markers with the MTE. METHODS Formalin-fixed paraffin-embedded tumor resection specimens of ten EC patients were analyzed using multiplex immunofluorescence staining. Since gold fiducial markers had been endoscopically implanted at the proximal and distal tumor borders prior to NRCHT+R, correlation of the markers with the MTE was feasible. RESULTS In tumor resection specimens of EC patients, the overall percentages of FAK+, CD44+, HIF-1α+, and Ki67+ cells were higher in tumor nests than in the tumor stroma, with the outcome for Ki67+ cells reaching statistical significance (p < 0.001). Conversely, expression of ILK+ cells was higher in tumor stroma, albeit not statistically significantly. In three patients, MTE beyond the fiducial markers was found, reaching up to 31 mm. CONCLUSION Our findings indicate that the overall expression of FAK, HIF-1α, Ki67, and CD44 was higher in tumor nests, whereas that of ILK was higher in tumor stroma. Differences in the TME between patients with residual tumor cells in the original CTV compared to those without were not found. Thus, there is insufficient evidence that the TME influences the required CTV margin on an individual patient basis. TRIAL REGISTRATION NUMBER AND DATE BO-EK-148042017 and BO-EK-177042022 on 20.06.2022, DRKS00011886, https://drks.de/search/de/trial/DRKS00011886 .
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Affiliation(s)
- Benjamin Terfa Igbo
- Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Christina Jentsch
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Annett Linge
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Ioana Plesca
- Institute of immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Yalçin Kuzay
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Steffen Löck
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Mani Sankari Kumaravadivel
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
| | - Susanne Doms
- Institute of immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Liane Stolz-Kieslich
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
| | - Daniela Pollack
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
| | - Sascha Brückmann
- Institute for Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Hannes Tittlbach
- Institute for Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jürgen Weitz
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
- Department of Visceral, Thoracic and Vascular Surgery (VTG), Faculty of Medicine and University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Daniela Aust
- Institute of immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Institute for Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Rudi Apolle
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Marc Schmitz
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
- Institute of immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Esther G C Troost
- Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
- Institute for Pathology and Tumor and Normal Tissue Bank of the University Cancer Center (UCC), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
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Vascular mimicry: A potential therapeutic target in breast cancer. Pathol Res Pract 2022; 234:153922. [DOI: 10.1016/j.prp.2022.153922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/19/2022] [Accepted: 04/24/2022] [Indexed: 10/18/2022]
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Xu Y, Fu L, Pan D, Wei J, Xia H, Wang S, Sun G. Folic Acid Inhibited Vasculogenic Mimicry in Esophageal Cancer Cell Line Eca-109, the One Target Was EphA2. Nutr Cancer 2021; 74:2235-2242. [PMID: 34678082 DOI: 10.1080/01635581.2021.1988992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 10/20/2022]
Abstract
The degree of vasculogenic mimicry(VM) is correlated with the prognosis of esophageal cancer, and folic acid supplementation could decrease esophagus cancer deaths among populations. This study aimed to explore the effect of folic acid on VM formation of esophageal cancer cell, and the target. Human esophageal squamous cancer cell lines(Eca-109) were cultured with different concentrations of folic acid (0,1,10,100,200,400, 600,800 μg/ml). A cell counting kit-8 (CCK-8) assay was used to measure the cell proliferation. Then, the amount of VM under the effect of different concentrations of folic acid was observed. Target genes were screened out from several possible targets genes including MMP2, MMP9, EphA2, VE-cad or Ln-5γ2 by employing reverse transcription-quantitative polymerase chain reaction(RT-qPCR). Finally, western blot analysis was used to verify the target proteins. In conclusion, this study found that folic acid inhibited the formation of VM in Eca-109 cells, and the one target protein was EphA2.
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Affiliation(s)
- YuLing Xu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - LingMeng Fu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - Da Pan
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - Jie Wei
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - Hui Xia
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - ShaoKang Wang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
| | - GuiJu Sun
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China
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Davern M, Donlon NE, Power R, Hayes C, King R, Dunne MR, Reynolds JV. The tumour immune microenvironment in oesophageal cancer. Br J Cancer 2021; 125:479-494. [PMID: 33903730 PMCID: PMC8368180 DOI: 10.1038/s41416-021-01331-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 01/16/2021] [Accepted: 02/17/2021] [Indexed: 02/02/2023] Open
Abstract
Oesophageal cancer (OC) is an inflammation-associated malignancy linked to gastro-oesophageal reflux disease, obesity and tobacco use. Knowledge of the microenvironment of oesophageal tumours is relevant to our understanding of the development of OC and its biology, and has major implications for understanding the response to standard therapies and immunotherapies, as well as for uncovering novel targets. In this context, we discuss what is known about the TME in OC from tumour initiation to development and progression, and how this is relevant to therapy sensitivity and resistance in the two major types of OC. We provide an immunological characterisation of the OC TME and discuss its prognostic implications with specific comparison with the Immunoscore and immune-hot, -cold, altered-immunosuppressed and -altered-excluded models. Targeted therapeutics for the TME under pre-clinical and clinical investigation in OCs are also summarised. A deeper understanding of the TME will enable the development of combination approaches to concurrently target the tumour cells and TME delivering precision medicine to OC patients.
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Affiliation(s)
- Maria Davern
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland
| | - Noel E Donlon
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland
| | - Robert Power
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland
| | - Conall Hayes
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland
| | - Ross King
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland
| | - Margaret R Dunne
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland
| | - John V Reynolds
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland.
- Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.
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King R, Hayes C, Donohoe CL, Dunne MR, Davern M, Donlon NE. Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers. World J Gastrointest Oncol 2021; 13:312-331. [PMID: 34040696 PMCID: PMC8131902 DOI: 10.4251/wjgo.v13.i5.312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/24/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases. This review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of GOCs. We focus on its bidirectional influence on inflammation and how it drives angiogenesis, innate and adaptive immune evasion, metastasis, and the reprogramming of cellular bioenergetics. The contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxia-targeted therapeutics is given. The principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.
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Affiliation(s)
- Ross King
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Conall Hayes
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Claire L Donohoe
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Margaret R Dunne
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Maria Davern
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Noel E Donlon
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
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Hujanen R, Almahmoudi R, Karinen S, Nwaru BI, Salo T, Salem A. Vasculogenic Mimicry: A Promising Prognosticator in Head and Neck Squamous Cell Carcinoma and Esophageal Cancer? A Systematic Review and Meta-Analysis. Cells 2020; 9:cells9020507. [PMID: 32102317 PMCID: PMC7072765 DOI: 10.3390/cells9020507] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 12/24/2022] Open
Abstract
Vasculogenic mimicry (VM) is an intratumoral microcirculation pattern formed by aggressive cancer cells, which mediates tumor growth. In this study, we compiled the evidence from studies evaluating whether positive VM status can serve as a prognostic factor to patients with squamous cell carcinoma of the head and neck (HNSCC) or esophagus (ESCC). Comprehensive systematic searches were conducted using Cochrane Library, Ovid Medline, PubMed, and Scopus databases. We appraised the quality of studies and the potential for bias, and performed random-effect meta-analysis to assess the prognostic impact of VM on the overall survival (OS). Seven studies with 990 patients were eligible, where VM was detected in 34.24% of patients. Positive-VM was strongly associated with poor OS (hazard ratio = 0.50; 95% confidence interval: 0.38-0.64), which remained consistent following the subgroup analysis of the studies. Furthermore, VM was associated with more metastasis to local lymph nodes and more advanced stages of HNSCC and ESCC. In conclusion, this study provides clear evidence showing that VM could serve as a promising prognosticator for patients with either HNSCC or ESCC. Further studies are warranted to assess how VM can be implemented as a reliable staging element in clinical practice and whether it could provide a new target for therapeutic intervention.
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Affiliation(s)
- Roosa Hujanen
- Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014 Helsinki, Finland
| | - Rabeia Almahmoudi
- Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014 Helsinki, Finland
| | - Sini Karinen
- Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014 Helsinki, Finland
| | - Bright I. Nwaru
- Krefting Research Centre, Institute of Medicine, University of Gothenburg, 40530 Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, Institute of Medicine, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Tuula Salo
- Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014 Helsinki, Finland
- Translational Immunology Research Program (TRIMM), Research Program Unit (RPU), University of Helsinki, 00014 Helsinki, Finland
- Cancer and Translational Medicine Research Unit, University of Oulu, 90014 Oulu, Finland
- Medical Research Centre, Oulu University Hospital, 90220 Oulu, Finland
- Helsinki University Hospital (HUS), 00029 Helsinki, Finland
| | - Abdelhakim Salem
- Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014 Helsinki, Finland
- Translational Immunology Research Program (TRIMM), Research Program Unit (RPU), University of Helsinki, 00014 Helsinki, Finland
- Correspondence:
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Valdivia A, Mingo G, Aldana V, Pinto MP, Ramirez M, Retamal C, Gonzalez A, Nualart F, Corvalan AH, Owen GI. Fact or Fiction, It Is Time for a Verdict on Vasculogenic Mimicry? Front Oncol 2019; 9:680. [PMID: 31428573 PMCID: PMC6688045 DOI: 10.3389/fonc.2019.00680] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/10/2019] [Indexed: 12/12/2022] Open
Abstract
The term vasculogenic mimicry (VM) refers to the capacity of certain cancer cells to form fluid-conducting structures within a tumor in an endothelial cell (EC)-free manner. Ever since its first report by Maniotis in 1999, the existence of VM has been an extremely contentious issue. The overwhelming consensus of the literature suggests that VM is frequently observed in highly aggressive tumors and correlates to lower patient survival. While the presence of VM in vivo in animal and patient tumors are claimed upon the strong positive staining for glycoproteins (Periodic Acid Schiff, PAS), it is by no means universally accepted. More controversial still is the existence of an in vitro model of VM that principally divides the scientific community. Original reports demonstrated that channels or tubes occur in cancer cell monolayers in vitro when cultured in matrigel and that these structures may support fluid movement. However, several years later many papers emerged stating that connections formed between cancer cells grown on matrigel represented VM. We speculate that this became accepted by the cancer research community and now the vast majority of the scientific literature reports both presence and mechanisms of VM based on intercellular connections, not the presence of fluid conducting tubes. In this opinion paper, we call upon evidence from an exhaustive review of the literature and original data to argue that the majority of in vitro studies presented as VM do not correspond to this phenomenon. Furthermore, we raise doubts on the validity of concluding the presence of VM in patient samples and animal models based solely on the presence of PAS+ staining. We outline the requirement for new biomarkers of VM and present criteria by which VM should be defined in vitro and in vivo.
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Affiliation(s)
- Andrés Valdivia
- Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gabriel Mingo
- Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Varina Aldana
- Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mauricio P Pinto
- Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Ramirez
- Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Claudio Retamal
- Faculty of Medicine and Science, Center of Cellular Biology and Biomedicine (CEBICEM), Universidad San Sebastian, Santiago, Chile
| | - Alfonso Gonzalez
- Faculty of Medicine and Science, Center of Cellular Biology and Biomedicine (CEBICEM), Universidad San Sebastian, Santiago, Chile
| | - Francisco Nualart
- Faculty of Biological Sciences, Universidad de Concepcion, Concepción, Chile
| | - Alejandro H Corvalan
- Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
| | - Gareth I Owen
- Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.,Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
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Correlation Between Tumor Vasculogenic Mimicry and Poor Prognosis of Human Digestive Cancer Patients: A Systematic Review and Meta-Analysis. Pathol Oncol Res 2018; 25:849-858. [PMID: 30361906 DOI: 10.1007/s12253-018-0496-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 10/10/2018] [Indexed: 12/12/2022]
Abstract
Vasculogenic mimicry (VM) is a new pattern of blood supplement independent of endothelial vessels, which is related with tumor invasion, metastasis and prognosis. However, the role of VM in the prognosis of cancer patients is controversial. This study aimed to perform a meta-analysis of the published data to attempt to clarify the prognostic value of VM in the digestive cancer. Relevant studies were retrieved from the PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure and VIP databases published before March 29, 2018. Studies were included if they detected VM in the digestive cancer and analyzed the overall survival (OS) or disease-free survival (DFS) according to VM status. Two independent reviewers screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was performed using STATA 12.0 software. A total of 22 studies with 2411 patients were included in this meta-analysis. Meta-analysis showed that VM was related with the poor OS (HR = 2.30, 95% CI: 2.06-2.56, P < 0.001) and DFS (HR = 2.60, 95% CI: 2.07-3.27, P < 0.001) of patients with digestive cancer. Subgroup analysis showed VM was related with tumor differentiation, lymph node metastasis and TNM stage. Moreover, the present meta-analysis was reliable, and there was no obvious publication bias. This meta-analysis suggested that VM was a poor prognosis of digestive cancer patients. Further large and well-designed studies are required.
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9
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Jing SW, Wang J, Xu Q. Expression of hypoxia inducible factor 1 alpha and its clinical significance in esophageal carcinoma: A meta-analysis. Tumour Biol 2017; 39:1010428317717983. [PMID: 28671053 DOI: 10.1177/1010428317717983] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Many studies have analyzed the relationship between hypoxia inducible factor 1 alpha expression and its relation to differentiation, lymph node metastasis, and other clinicopathological variables of esophageal carcinoma, but the results are still inconsistent. This meta-analysis was carried out to explore hypoxia inducible factor 1 alpha in esophageal carcinoma and its correlation with clinicopathological features and prognosis, in order to provide comprehensive reference for clinic. A total of 18 studies including 1566 patients with esophageal squamous cell carcinoma were enrolled. The results showed that compared with para-carcinoma tissue, the expression of hypoxia inducible factor 1 alpha was significantly enhanced (odds ratio = 0.122, 95% confidence interval = 0.074-0.201, p = 0.000); hypoxia inducible factor 1 alpha was associated with differentiation (odds ratio = 1.458, 95% confidence interval = 1.108-1.920, p = 0.007), T classification (odds ratio = 0.457, 95% confidence interval = 0.265-0.786, p = 0.005), lymph node metastasis (odds ratio = 0.337, 95% confidence interval = 0.185-0.614, p = 0.000), and pathological tumor-node-metastasis stage (odds ratio = 0.362, 95% confidence interval = 0.177-0.740, p = 0.005), whereas there was no relation to histological grade, lymphatic vessel invasion, blood vessel invasion, 3- to 5-year overall survival and disease-free survival. Patients with hypoxia inducible factor 1 alpha overexpression had poor differentiation, increased depth of tumor invasion, more lymph node metastasis, and late pathological tumor-node-metastasis stage. Hypoxia inducible factor 1 alpha could be an indicator for differentiation, T classification, lymph node metastasis, and pathological tumor-node-metastasis stage, and it is worth further study.
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Affiliation(s)
- Shao Wu Jing
- 1 Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Wang
- 1 Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qing Xu
- 2 Department of Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Novel insight into triple-negative breast cancers, the emerging role of angiogenesis, and antiangiogenic therapy. Expert Rev Mol Med 2016; 18:e18. [PMID: 27817751 DOI: 10.1017/erm.2016.17] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours characterised by lack of expression of oestrogen-, progesterone- and human epidermal growth factor receptors. TNBC, which represents approximately 15% of all mammary tumours, has a poor prognosis because of an aggressive behaviour and the lack of specific treatment. Accordingly, TNBC has become a major focus of research into breast cancer and is now classified into several molecular subtypes, each with a different prognosis. Pathological angiogenesis occurs at a late stage in the proliferation of TNBC and is associated with invasion and metastasis; there is an association with metabolic syndrome. Semaphorins are a versatile family of proteins with multiple roles in angiogenesis, tumour growth and metastasis and may represent a clinically useful focus for therapeutic targeting in this type of breast cancer. Another important field of investigation into the control of pathological angiogenesis is related to the expression of noncoding RNA (ncRNA) – these molecules can be considered as a therapeutic target or as a biomarker. Several molecular agents for intervening in the activity of different signalling pathways are being explored in TNBC, but none has so far proved effective in clinical trials and the disease continues to pose a defining challenge for clinical management as well as innovative cancer research.
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11
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Bao ZQ, Zhang CC, Xiao YZ, Zhou JS, Tao YS, Chai DM. Over-expression of Sox4 and β-catenin is associated with a less favorable prognosis of osteosarcoma. ACTA ACUST UNITED AC 2016; 36:193-199. [PMID: 27072961 DOI: 10.1007/s11596-016-1565-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 10/20/2015] [Indexed: 12/17/2022]
Abstract
The purpose of this study was to examine the association of the expression of Sox4 and β-catenin with the prognosis of osteosarcoma. A total of 108 cases of conventional osteosarcoma were involved in this study and 28 cases of osteochondroma served as controls. The expression of Sox4 and β-catenin was detected by using immunohistochemical staining and Western blotting. The results showed that Sox4 and β-catenin were over-expressed in 67 (62.03%) and 62 (57.41%) of 108 osteosarcoma cases, while in only 3 (10.71%) and 5 (17.86%) of 28 controls, respectively (P<0.05 for all). The expression of Sox4 and β-catenin was associated with the distant metastasis, pathological grade and Enneking stage of patients with osteosarcoma (P<0.05 for all). The mean overall survival time and the 5-year-survival rate in osteosarcoma patients with Sox4 and β-catenin over-expressed were significantly reduced as compared with those in Sox4 and β-catenin low-expression group (P<0.05 for all). Cox multifactor regression analysis revealed that the distant metastasis, Enneking stage, and the expression of Sox4 and β-catenin were independent risk factors of patients with osteosarcoma (P<0.05 for all). The findings indicated that overexpression of Sox4 and β-catenin is associated with a poor prognosis of osteosarcoma.
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Affiliation(s)
- Zheng-Qi Bao
- Department of Orthopaedics, the First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
| | - Chang-Chun Zhang
- Department of Orthopaedics, the First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
| | - Yu-Zhou Xiao
- Department of Orthopaedics, the First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
| | - Jian-Sheng Zhou
- Department of Orthopaedics, the First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
| | - Yi-Sheng Tao
- Department of Pathology, the First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
| | - Da-Min Chai
- Department of Pathology, the First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China.
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Tumor vasculogenic mimicry predicts poor prognosis in cancer patients: a meta-analysis. Angiogenesis 2016; 19:191-200. [DOI: 10.1007/s10456-016-9500-2] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 02/11/2016] [Indexed: 01/10/2023]
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13
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Yang JS, Wang T, Qiu MQ, Li QL. Comparison of efficacy and toxicity profiles between paclitaxel/lobapoatin- and cisplatin/5-fluorouracil-based concurrent chemoradiotherapy of advanced inoperable oesophageal cancer. Intern Med J 2015; 45:757-61. [PMID: 25851492 DOI: 10.1111/imj.12773] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 03/24/2015] [Indexed: 12/22/2022]
Affiliation(s)
- J-S. Yang
- Department of Medical Oncology; Zaozhuang Municipal Hospital; Zaozhuang China
| | - T. Wang
- Department of Medical Oncology; Zaozhuang Municipal Hospital; Zaozhuang China
| | - M-Q. Qiu
- Department of Medical Oncology; Zaozhuang Municipal Hospital; Zaozhuang China
| | - Q-L. Li
- Department of Medical Oncology; Zaozhuang Municipal Hospital; Zaozhuang China
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Tian Y, Hao S, Ye M, Zhang A, Nan Y, Wang G, Jia Z, Yu K, Guo L, Pu P, Huang Q, Zhong Y. MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly. Biochem Biophys Res Commun 2015; 458:307-12. [PMID: 25656572 DOI: 10.1016/j.bbrc.2015.01.105] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 01/22/2015] [Indexed: 01/11/2023]
Abstract
We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brain tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin.
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Affiliation(s)
- Yuan Tian
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China; Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government, People's Republic of China
| | - Shaobo Hao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China; Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government, People's Republic of China
| | - Minhua Ye
- Department of Neurosurgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, People's Republic of China
| | - Anling Zhang
- Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China; Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government, People's Republic of China
| | - Yang Nan
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Guangxiu Wang
- Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China; Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government, People's Republic of China
| | - Zhifan Jia
- Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China; Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government, People's Republic of China
| | - Kai Yu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Lianmei Guo
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Peiyu Pu
- Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, People's Republic of China; Key Laboratory of Neurotrauma, Variation and Regeneration, Ministry of Education and Tianjin Municipal Government, People's Republic of China
| | - Qiang Huang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.
| | - Yue Zhong
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.
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Tang NN, Zhu H, Zhang HJ, Zhang WF, Jin HL, Wang L, Wang P, He GJ, Hao B, Shi RH. HIF-1α induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells. World J Gastroenterol 2014; 20:17894-17904. [PMID: 25548487 PMCID: PMC4273139 DOI: 10.3748/wjg.v20.i47.17894] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 04/03/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether hypoxia inducible factor (HIF)-1α modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC). METHODS Esophageal squamous cancer cell lines Eca109 and TE13 were transfected with plasmids harboring small interfering RNAs targeting HIF-1α or VE-cadherin. The proliferation and invasion of esophageal carcinoma cells were detected by MTT and Transwell migration assays. The formation of tubular networks of cells was analyzed by 3D culture in vitro. BALB/c nude mice were used to observe xenograft tumor formation. The relationship between the expression of HIF-1α and VE-cadherin, ephrinA2 (EphA2) and laminin5γ2 (LN5γ2) was measured by Western blot and real-time polymerase chain reaction. RESULTS Knockdown of HIF-1α inhibited cell proliferation (32.3% ± 6.1% for Eca109 cells and 38.6% ± 6.8% for TE13 cells, P < 0.05). Both Eca109 and TE13 cells formed typical tubular networks. The number of tubular networks markedly decreased when HIF-1α or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5γ2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1α-silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5γ2 (P < 0.05), while HIF-1α expression was unchanged. The time for xenograft tumor formation was 6 ± 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1α Neo control short hairpin RNA (shRNA) vector, and 8.4 ± 2.1 d for Eca109 cells transfected with an shRNA against HIF-1α. Knockdown of HIF-1α inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo. CONCLUSION HIF-1α may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5γ2.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Apoptosis
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Squamous Cell/blood supply
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Esophageal Neoplasms/blood supply
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Esophageal Squamous Cell Carcinoma
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Laminin/genetics
- Laminin/metabolism
- Mice, Inbred BALB C
- Mice, Nude
- Molecular Mimicry
- Neoplasm Invasiveness
- Neovascularization, Pathologic
- RNA Interference
- Receptor, EphA2/genetics
- Receptor, EphA2/metabolism
- Signal Transduction
- Time Factors
- Transfection
- Tumor Burden
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Lezcano C, Kleffel S, Lee N, Larson AR, Zhan Q, DoRosario A, Wang LC, Schatton T, Murphy GF. Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts. J Transl Med 2014; 94:1092-102. [PMID: 25111691 PMCID: PMC4236190 DOI: 10.1038/labinvest.2014.99] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 06/24/2014] [Accepted: 06/27/2014] [Indexed: 12/31/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents.
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Affiliation(s)
- Cecilia Lezcano
- Department of Pathology, University of Pittsburgh Medical Center,
Pittsburgh, PA
| | - Sonja Kleffel
- Department of Dermatology, Brigham and Women’s Hospital,
Boston, MA,Harvard Medical School, Boston, MA
| | - Nayoung Lee
- Department of Dermatology, Brigham and Women’s Hospital,
Boston, MA,Harvard Medical School, Boston, MA
| | - Allison R. Larson
- Department of Dermatology, Brigham and Women’s Hospital,
Boston, MA,Harvard Medical School, Boston, MA
| | - Qian Zhan
- Harvard Medical School, Boston, MA,Department of Pathology, Brigham and Women’s Hospital,
Boston, MA
| | - Andrew DoRosario
- Harvard Medical School, Boston, MA,Center for Cutaneous Oncology, Dana-Farber/Brigham and
Women’s Cancer Center, Boston, MA
| | - Linda C. Wang
- Institute for Cancer Care, Mercy Medical Center, Baltimore,
MD
| | - Tobias Schatton
- Harvard Medical School, Boston, MA,Transplantation Research Center, Children’s Hospital
Boston, MA
| | - George F. Murphy
- Harvard Medical School, Boston, MA,Department of Pathology, Brigham and Women’s Hospital,
Boston, MA
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17
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Sui H, Zhu L, Deng W, Li Q. Epithelial-mesenchymal transition and drug resistance: role, molecular mechanisms, and therapeutic strategies. Oncol Res Treat 2014; 37:584-9. [PMID: 25342509 DOI: 10.1159/000367802] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 07/31/2014] [Indexed: 11/19/2022]
Abstract
Chemotherapy is an important therapeutic option for most cancer patients; however, one major obstacle is the occurrence of drug resistance which usually leads to failure of the chemotherapy. Emerging evidence suggests that there are intricate links between epithelial-mesenchymal transition (EMT)-type cells and drug resistance in tumors. The process of drug resistance can be regulated by a diverse array of cytokines and growth factors, higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug efflux transporters. Moreover, recent reports have indicated that the emergence of drug resistance may occur as a result of EMT. In this regard, most drug-resistant cancers contain a subpopulation of cells with stem-like and mesenchymal features that are resistant to chemotherapy. In this review, we will explain potential mechanisms for the association between EMT induction and the emergence of drug resistance, and discuss new approaches and drugs for the clinical management of drug-resistant cancer induced by EMT.
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Affiliation(s)
- Hua Sui
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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18
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Brocato J, Chervona Y, Costa M. Molecular responses to hypoxia-inducible factor 1α and beyond. Mol Pharmacol 2014; 85:651-7. [PMID: 24569087 PMCID: PMC3990019 DOI: 10.1124/mol.113.089623] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 02/25/2014] [Indexed: 12/14/2022] Open
Abstract
Cellular response to changes in oxygen tension during normal development or pathologic processes is, in part, regulated by hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor. HIF activity is primarily controlled through post-translational modifications and stabilization of HIF-1α and HIF-2α proteins and is regulated by a number of cellular pathways involving both oxygen-dependent and -independent mechanisms. Stabilization of HIF-1α activates transcription of genes that participate in key pathways in carcinogenesis, such as angiogenesis, dedifferentiation, and invasion. Since its discovery more than two decades ago, HIF-1α has become a hot topic in molecular research and has been implicated not only in disease pathology but also in prognosis. In this review, we will focus on recent insights into HIF-1α regulation, function, and gene expression. We will also discuss emerging data on the involvement of HIF in cancer prognosis and therapeutic interventions.
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Affiliation(s)
- Jason Brocato
- Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York
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