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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Surguta SE, Baranyi M, Svajda L, Cserepes M, Ranđelović I, Tátrai E, Hegedűs B, Tóvári J. Differential effects of hypoxia on motility using various in vitro models of lung adenocarcinoma. Sci Rep 2024; 14:20482. [PMID: 39227650 PMCID: PMC11372077 DOI: 10.1038/s41598-024-70769-w] [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: 02/20/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024] Open
Abstract
Lung cancer is the leading cause of cancer-related death globally. Metastasis is the most common reason of mortality in which hypoxia is suggested to have a pivotal role. However, the effect of hypoxia on the metastatic potential and migratory activity of cancer cells is largely unexplored and warrants detailed scientific investigations. Accordingly, we analyzed changes on cell proliferation and migratory activity both in single-cell migration and invasion under normoxic and hypoxic conditions in lung adenocarcinoma cell lines. Alterations in crucial genes and proteins associated with cellular response to hypoxia, epithelial-mesenchymal transition, proliferation and apoptosis were also analyzed. Generally, we observed no change in proliferation upon hypoxic conditions and no detectable induction of apoptosis. Interestingly, we observed that single-cell motility was generally reduced while invasion under confluent conditions using scratch assay was enhanced by hypoxia in most of the cell lines. Furthermore, we detected changes in the expression of EMT markers that are consistent with enhanced motility and metastasis-promoting effect of hypoxia. In summary, our study indicated cell line-, time of exposure- and migrational type-dependent effects of hypoxia in cellular proliferation, motility and gene expression. Our results contribute to better understanding and tackling cancer metastasis.
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Affiliation(s)
- Sára Eszter Surguta
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary.
- School of Ph.D. Studies, Semmelweis University, Budapest, 1085, Hungary.
| | - Marcell Baranyi
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, 1091, Hungary
| | - Laura Svajda
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
- School of Ph.D. Studies, Semmelweis University, Budapest, 1085, Hungary
| | - Mihály Cserepes
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Ivan Ranđelović
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Enikő Tátrai
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
| | - Balázs Hegedűs
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, 1091, Hungary
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, 45239, Essen, Germany
| | - József Tóvári
- Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary
- School of Ph.D. Studies, Semmelweis University, Budapest, 1085, Hungary
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Lue KH, Chen YH, Chu SC, Lin CB, Wang TF, Liu SH. Prognostic value of combining clinical factors, 18F-FDG PET-based intensity, volumetric features, and deep learning predictor in patients with EGFR-mutated lung adenocarcinoma undergoing targeted therapies: a cross-scanner and temporal validation study. Ann Nucl Med 2024; 38:647-658. [PMID: 38704786 DOI: 10.1007/s12149-024-01936-2] [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: 03/07/2024] [Accepted: 04/22/2024] [Indexed: 05/07/2024]
Abstract
OBJECTIVE To investigate the prognostic value of 18F-FDG PET-based intensity, volumetric features, and deep learning (DL) across different generations of PET scanners in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving tyrosine kinase inhibitor (TKI) treatment. METHODS We retrospectively analyzed the pre-treatment 18F-FDG PET of 217 patients with advanced-stage lung adenocarcinoma and actionable EGFR mutations who received TKI as first-line treatment. Patients were separated into analog (n = 166) and digital (n = 51) PET cohorts. 18F-FDG PET-derived intensity, volumetric features, ResNet-50 DL of the primary tumor, and clinical variables were used to predict progression-free survival (PFS). Independent prognosticators were used to develop prediction model. Model was developed and validated in the analog and digital PET cohorts, respectively. RESULTS In the analog PET cohort, female sex, stage IVB status, exon 19 deletion, SUVmax, metabolic tumor volume, and positive DL prediction independently predicted PFS. The model devised from these six prognosticators significantly predicted PFS in the analog (HR = 1.319, p < 0.001) and digital PET cohorts (HR = 1.284, p = 0.001). Our model provided incremental prognostic value to staging status (c-indices = 0.738 vs. 0.558 and 0.662 vs. 0.598 in the analog and digital PET cohorts, respectively). Our model also demonstrated a significant prognostic value for overall survival (HR = 1.198, p < 0.001, c-index = 0.708 and HR = 1.256, p = 0.021, c-index = 0.664 in the analog and digital PET cohorts, respectively). CONCLUSIONS Combining 18F-FDG PET-based intensity, volumetric features, and DL with clinical variables may improve the survival stratification in patients with advanced EGFR-mutated lung adenocarcinoma receiving TKI treatment. Implementing the prediction model across different generations of PET scanners may be feasible and facilitate tailored therapeutic strategies for these patients.
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Affiliation(s)
- Kun-Han Lue
- Department of Medical Imaging and Radiological Sciences, Tzu Chi University of Science and Technology, No.880, Sec.2, Chien-kuo Rd., Hualien, 970302, Taiwan
| | - Yu-Hung Chen
- Department of Medical Imaging and Radiological Sciences, Tzu Chi University of Science and Technology, No.880, Sec.2, Chien-kuo Rd., Hualien, 970302, Taiwan.
- Department of Nuclear Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No.707, Sec.3, Zhongyang Rd, Hualien, 970473, Taiwan.
- School of Medicine, College of Medicine, Tzu Chi University, No.701, Sec.3, Zhongyang Rd, Hualien, 970473, Taiwan.
| | - Sung-Chao Chu
- School of Medicine, College of Medicine, Tzu Chi University, No.701, Sec.3, Zhongyang Rd, Hualien, 970473, Taiwan
- Department of Hematology and Oncology, Buddhist Tzu Chi Medical Foundation, Hualien Tzu Chi Hospital, Hualien, Taiwan
| | - Chih-Bin Lin
- School of Medicine, College of Medicine, Tzu Chi University, No.701, Sec.3, Zhongyang Rd, Hualien, 970473, Taiwan
- Department of Internal Medicine, Buddhist Tzu Chi Medical Foundation, Hualien Tzu Chi Hospital, Hualien, Taiwan
| | - Tso-Fu Wang
- School of Medicine, College of Medicine, Tzu Chi University, No.701, Sec.3, Zhongyang Rd, Hualien, 970473, Taiwan
- Department of Hematology and Oncology, Buddhist Tzu Chi Medical Foundation, Hualien Tzu Chi Hospital, Hualien, Taiwan
| | - Shu-Hsin Liu
- Department of Medical Imaging and Radiological Sciences, Tzu Chi University of Science and Technology, No.880, Sec.2, Chien-kuo Rd., Hualien, 970302, Taiwan
- Department of Nuclear Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No.707, Sec.3, Zhongyang Rd, Hualien, 970473, Taiwan
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Ubaid S, Kashif M, Laiq Y, Nayak AK, Kumar V, Singh V. Targeting HIF-1α in sickle cell disease and cancer: unraveling therapeutic opportunities and risks. Expert Opin Ther Targets 2024; 28:357-373. [PMID: 38861226 DOI: 10.1080/14728222.2024.2367640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 06/10/2024] [Indexed: 06/12/2024]
Abstract
INTRODUCTION HIF-1α, a key player in medical science, holds immense significance in therapeutic approaches. This review delves into its complex dynamics, emphasizing the delicate balance required for its modulation. HIF-1α stands as a cornerstone in medical research, its role extending to therapeutic strategies. This review explores the intricate interplay surrounding HIF-1α, highlighting its critical involvement and the necessity for cautious modulation. AREAS COVERED In sickle cell disease (SCD), HIF-1α's potential to augment fetal hemoglobin (HbF) production and mitigate symptoms is underscored. Furthermore, its role in cancer is examined, particularly its influence on survival in hypoxic tumor microenvironments, angiogenesis, and metastasis. The discussion extends to the intricate relationship between HIF-1α modulation and cancer risks in SCD patients, emphasizing the importance of balancing therapeutic benefits and potential hazards. EXPERT OPINION Managing HIF-1α modulation in SCD patients requires a nuanced approach, considering therapeutic potential alongside associated risks, especially in exacerbating cancer risks. An evolutionary perspective adds depth, highlighting adaptations in populations adapted to low-oxygen environments and aligning cancer cell metabolism with primitive cells. The role of HIF-1α as a therapeutic target is discussed within the context of complex cancer biology and metabolism, acknowledging varied responses across diverse cancers influenced by intricate evolutionary adaptations.
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Affiliation(s)
- Saba Ubaid
- Department of Biochemistry, King George's Medical University, Lucknow, India
| | - Mohammad Kashif
- Infectious Diseases Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Yusra Laiq
- Department of Biotechnology, Era University, Lucknow, India
| | | | - Vipin Kumar
- Infectious Diseases Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Vivek Singh
- Department of Biochemistry, King George's Medical University, Lucknow, India
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Sun W, Cheng Y, Ma X, Jin Z, Zhang Q, Wang G. Photodynamic therapy upregulates expression of HIF-1α and PD-L1 in related pathways and its clinical relevance in non-small-cell lung cancer. Eur J Med Res 2024; 29:230. [PMID: 38609977 PMCID: PMC11015541 DOI: 10.1186/s40001-024-01780-0] [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: 11/02/2023] [Accepted: 03/10/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Photodynamic therapy (PDT) is a promising interventional treatment approach that contributes to antitumor immunity. It has been reported that PDT can enhance the effectiveness of immune checkpoint inhibitors (ICIs), but its mechanism is yet unclear. Herein, we implemented bioinformatics analysis to detect common pathways and potential biomarkers in non-small cell lung cancer (NSCLC), PDT, and NSCLC immunotherapy to investigate potential links between PDT, immunotherapy and NSCLC, and their clinical impact. METHODS Differentially expressed genes in NSCLC- and NSCLC immunotherapy-related data in the GEO database were intersected with PDT-related genes in the GeneCards database to obtain candidate genes and shared pathways. Enrichment analysis and protein-protein interaction were established to identify key genes in functionally enriched pathways. The expression profiles and the prognostic significance of key genes were depicted. RESULTS Bioinformatics analysis showed that HIF-1α was screened as a prognostic gene in hypoxia, HIF-1, and PD-L1-related signaling pathways, which was associated with clinical response in NSCLC patients after PDT and immunotherapy. In vivo experiments showed that PDT could inhibit tumor growth and upregulate HIF-1α and PD-L1 expressions in NSCLC tissues with a positive correlation, which might influence the blocking activity of ICIs on the HIF-1, and PD-L1-related signaling pathways. CONCLUSIONS PDT might improve the clinical response of ICIs by upregulating tumor HIF-1α and PD-L1 expressions in NSCLC.
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Affiliation(s)
- Wen Sun
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Yuan Cheng
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Xiaoyu Ma
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Zhou Jin
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Qi Zhang
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Guangfa Wang
- Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China.
- Department of Pulmonary and Critical Care Medicine, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
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Wei Y, Wang L, Jin Z, Jia Q, Brcic L, Akaba T, Chu Q. Biological characteristics and clinical treatment of pulmonary sarcomatoid carcinoma: a narrative review. Transl Lung Cancer Res 2024; 13:635-653. [PMID: 38601447 PMCID: PMC11002509 DOI: 10.21037/tlcr-24-127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 03/12/2024] [Indexed: 04/12/2024]
Abstract
Background and Objective Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. Methods For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Key Content and Findings Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Conclusions Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.
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Affiliation(s)
- Yuxuan Wei
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Wang
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Jin
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
- Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co., Ltd., Shanghai, China
| | - Qingzhu Jia
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Immunotherapy, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Luka Brcic
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Tomohiro Akaba
- Department of Respiratory Medicine, Tokyo Women’s Medical University, Tokyo, Japan
| | - Qian Chu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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ZHOU Y, REN D, BI H, YI B, ZHANG C, WANG H, SUN J. [Tumor-associated Macrophage:
Emerging Targets for Modulating the Tumor Microenvironment]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:231-240. [PMID: 38590197 PMCID: PMC11002190 DOI: 10.3779/j.issn.1009-3419.2024.102.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Indexed: 04/10/2024]
Abstract
Tumor-associated macrophage (TAM) play a crucial role in the immune microenvironment of lung cancer. Through changes in their phenotype and phagocytic functions, TAM contribute to the initiation and progression of lung cancer. By promoting the formation of an immune-suppressive microenvironment and accelerating the growth of abnormal tumor vasculature, TAM facilitate the invasion and metastasis of lung cancer. Macrophages can polarize into different subtypes with distinct functions and characteristics in response to various stimuli, categorized as anti-tumor M1 and pro-tumor M2 types. In tumor tissues, TAM typically polarize into the alternatively activated M2 phenotype, exhibiting inhibitory effects on tumor immunity. This article reviews the role of anti-angiogenic drugs in modulating TAM phenotypes, highlighting their potential to reprogram M2-type TAM into an anti-tumor M1 phenotype. Additionally, the functional alterations of TAM play a significant role in anti-angiogenic therapy and immunotherapy strategies. In summary, the regulation of TAM polarization and function opens up new avenues for lung cancer treatment and may serve as a novel target for modulating the immune microenvironment of tumors.
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Ildiz ES, Gvozdenovic A, Kovacs WJ, Aceto N. Travelling under pressure - hypoxia and shear stress in the metastatic journey. Clin Exp Metastasis 2023; 40:375-394. [PMID: 37490147 PMCID: PMC10495280 DOI: 10.1007/s10585-023-10224-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/05/2023] [Indexed: 07/26/2023]
Abstract
Cancer cell invasion, intravasation and survival in the bloodstream are early steps of the metastatic process, pivotal to enabling the spread of cancer to distant tissues. Circulating tumor cells (CTCs) represent a highly selected subpopulation of cancer cells that tamed these critical steps, and a better understanding of their biology and driving molecular principles may facilitate the development of novel tools to prevent metastasis. Here, we describe key research advances in this field, aiming at describing early metastasis-related processes such as collective invasion, shedding, and survival of CTCs in the bloodstream, paying particular attention to microenvironmental factors like hypoxia and mechanical stress, considered as important influencers of the metastatic journey.
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Affiliation(s)
- Ece Su Ildiz
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Werner J Kovacs
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland.
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Shafqat A, Omer MH, Ahmed EN, Mushtaq A, Ijaz E, Ahmed Z, Alkattan K, Yaqinuddin A. Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy. Front Immunol 2023; 14:1200941. [PMID: 37520562 PMCID: PMC10374407 DOI: 10.3389/fimmu.2023.1200941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/15/2023] [Indexed: 08/01/2023] Open
Abstract
This review focuses on the immunosuppressive effects of tumor angiogenesis and coagulation on the tumor microenvironment (TME). We summarize previous research efforts leveraging these observations and targeting these processes to enhance immunotherapy outcomes. Clinical trials have documented improved outcomes when combining anti-angiogenic agents and immunotherapy. However, their overall survival benefit over conventional therapy remains limited and certain tumors exhibit poor response to anti-angiogenic therapy. Additionally, whilst preclinical studies have shown several components of the tumor coagulome to curb effective anti-tumor immune responses, the clinical studies reporting combinations of anticoagulants with immunotherapies have demonstrated variable treatment outcomes. By reviewing the current state of the literature on this topic, we address the key questions and future directions in the field, the answers of which are crucial for developing effective strategies to reprogram the TME in order to further the field of cancer immunotherapy.
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Affiliation(s)
- Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Mohamed H. Omer
- School of Medicine, Cardiff University, Cardiff, United Kingdom
| | | | - Ali Mushtaq
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Eman Ijaz
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Zara Ahmed
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Khaled Alkattan
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Paudel KR, Manandhar B, Singh SK, Gupta G, Hansbro PM, Chellappan DK, Dua K. Cytotoxic mechanisms of berberine-phytantriol liquid crystalline nanoparticles against non-small-cell lung cancer. EXCLI JOURNAL 2023; 22:516-519. [PMID: 37534226 PMCID: PMC10390893 DOI: 10.17179/excli2023-6156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/15/2023] [Indexed: 08/04/2023]
Affiliation(s)
- Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2050, Australia
| | - Bikash Manandhar
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Sachin Kumar Singh
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura 302017, Mahal Road, Jaipur, India
- Center for Transdisciplinary Research, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun 248007, India
| | - Philip Michael Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2050, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
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The Role of Reprogrammed Glucose Metabolism in Cancer. Metabolites 2023; 13:metabo13030345. [PMID: 36984785 PMCID: PMC10051753 DOI: 10.3390/metabo13030345] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer cells reprogram their metabolism to meet biosynthetic needs and to adapt to various microenvironments. Accelerated glycolysis offers proliferative benefits for malignant cells by generating glycolytic products that move into branched pathways to synthesize proteins, fatty acids, nucleotides, and lipids. Notably, reprogrammed glucose metabolism and its associated events support the hallmark features of cancer such as sustained cell proliferation, hijacked apoptosis, invasion, metastasis, and angiogenesis. Overproduced enzymes involved in the committed steps of glycolysis (hexokinase, phosphofructokinase-1, and pyruvate kinase) are promising pharmacological targets for cancer therapeutics. In this review, we summarize the role of reprogrammed glucose metabolism in cancer cells and how it can be manipulated for anti-cancer strategies.
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Cunningham C, Bolcaen J, Bisio A, Genis A, Strijdom H, Vandevoorde C. Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2023; 16:219. [PMID: 37259367 PMCID: PMC9961924 DOI: 10.3390/ph16020219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 11/03/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in cancer progression. Several anti-angiogenic drugs, such as recombinant endostatin (RE), have been evaluated in several preclinical and clinical trials, with mixed and often disappointing results. However, there is currently an emerging interest in RE due to its ability to create a vascular normalization window, which could further improve treatment efficacy of the standard NSCLC treatment. This review provides an overview of preclinical and clinical studies that combined RE and radiotherapy for NSCLC treatment. Furthermore, it highlights the ongoing challenges that have to be overcome in order to maximize the benefit; as well as the potential advantage of combinations with particle therapy and immunotherapy, which are rapidly gaining momentum in the treatment landscape of NSCLC. Different angiogenic and immunosuppressive effects are observed between particle therapy and conventional X-ray radiotherapy. The combination of RE, particle therapy and immunotherapy presents a promising future therapeutic triad for NSCLC.
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Affiliation(s)
- Charnay Cunningham
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
- Radiation Biophysics Division, SSC Laboratory, NRF Ithemba LABS, Cape Town 7131, South Africa
| | - Julie Bolcaen
- Radiation Biophysics Division, SSC Laboratory, NRF Ithemba LABS, Cape Town 7131, South Africa
| | - Alessandra Bisio
- Department of Cellular, Computational and Integrative Biology—CIBIO, University of Trento, 38123 Trento, Italy
| | - Amanda Genis
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
| | - Hans Strijdom
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
| | - Charlot Vandevoorde
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung, Planckstr. 1, 64291 Darmstadt, Germany
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Shi S, Ye L, Yu X, Jin K, Wu W. Focus on mast cells in the tumor microenvironment: Current knowledge and future directions. Biochim Biophys Acta Rev Cancer 2023; 1878:188845. [PMID: 36476563 DOI: 10.1016/j.bbcan.2022.188845] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/01/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
Mast cells (MCs) are crucial cells participating in both innate and adaptive immune processes that play important roles in protecting human health and in the pathophysiology of various diseases, such as allergies, cardiovascular diseases, and autoimmune diseases. In the context of tumors, MCs are a non-negligible population of immune cells in the tumor microenvironment (TME). In most tumor types, MCs accumulate in both the tumor tissue and the surrounding tissue. MCs interact with multiple components of the TME, affecting TME remodeling and the tumor cell fate. However, controversy persists regarding whether MCs contribute to tumor progression or trigger an anti-tumor immune response. This review focuses on the context of the TME to explore the specific properties and functions of MCs and discusses the crosstalk that occurs between MCs and other components of the TME, which affect tumor angiogenesis and lymphangiogenesis, invasion and metastasis, and tumor immunity through different mechanisms. We also anticipate the potential role of MCs in cancer immunotherapy, which might expand upon the success achieved with existing cancer therapies.
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Affiliation(s)
- Saimeng Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Weiding Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
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14
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Wang L, Zhao X, Zheng H, Zhu C, Liu Y. AIF-1, a potential biomarker of aggressive tumor behavior in patients with non-small cell lung cancer. PLoS One 2022; 17:e0279211. [PMID: 36520870 PMCID: PMC9754194 DOI: 10.1371/journal.pone.0279211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
Allogeneic inflammatory factor-1 (AIF-1) overexpression has been reported to be associated with tumorigenesis and tumor metastasis. This study aimed to investigate the role of AIF-1 in the development and progression of non-small cell lung cancer (NSCLC). AIF-1, IL-6, and VEGF expressions in human NSCLC tissue were examined by immunofluorescence staining. Bioinformatics analyses were performed to identify AIF-1-related molecules and pathways in NSCLC. Human lung cancer A549 cell proliferation was assessed by CCK-8 assay, and cell migration was evaluated with wound-healing assay. IL-6 and VEGF secretions in A549 cell culture supernatants were quantified using the Elecsys IL-6 immunoassay kit and Vascular Endothelial Growth Factor Assay Kit. RT-PCR and western blot were performed to quantify the expressions of AIF-1, IL-6, and VEGF mRNAs and proteins involved in p38-MAPK and JAK/STAT3 signaling such as p-p38 and p-STAT3. The effects of AIF-1 on A549 cell proliferation and the expressions of IL-6 and VEGF were assessed using SB203580 and ruxolitinib. The results showed that AIF-1 expression was higher in human NSCLC tissue than that in paracancer tissue. High AIF-1 expression was associated with metastasis, higher TNM stage, and poorer survival. Bioinformatics connected AIF-1 to JAK/STAT signaling in NSCLC. AIF-1 increased A549 cell proliferation, migration, IL-6 secretion and, VEGF secretion, and these effects were attenuated by inhibition of p38-MAPK or JAK/STAT3 signaling. In conclusion, AIF-1 may promote aggressive NSCLC behavior via activation of p38-MAPK and JAK/STAT signaling.
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Affiliation(s)
- Lingling Wang
- Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Laboratory Diagnosis, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Xing Zhao
- Department of Pathology, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Cuimin Zhu
- Department of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Yanhong Liu
- Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- * E-mail:
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15
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Li J, Yan Y, Wang G, Huang Z. Hypoxia-inducible factor-2α and its missense mutations: potential role in HCC diagnosis, progression, and prognosis and underlying mechanism. ONCOLOGY AND TRANSLATIONAL MEDICINE 2022; 8:267-275. [DOI: 10.1007/s10330-022-0598-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 12/01/2022] [Indexed: 01/04/2025]
Abstract
Abstract
Objective
This study aims to gain further the potential mechanisms of HIF-2α in tumor progression and tumorigenesis.
Methods
Mined The Cancer Genome Atlas (TCGA) dataset. In total, 421 participants were enrolled in the TCGAHepatocellular Carcinoma (HCC) study, comprising 371 patients with cancer and 50 healthy controls. From the 371 tumor samples, three samples containing the missense mutation of the HIF-2α gene were compared with 368 wild-type samples to identify differentially expressed genes (DEGs).
Results
After filtering, univariate Cox regression and multivariate Cox regression analyses showed that the differentially expressed genes (DEGs) progestagen-associated endometrial protein (PAEP) PNLIPRP2, MIR147B, and pregnancy zone protein (PZP) were significantly correlated with the survival times of patients with HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8 database to detect the functional annotation of these four DEGs as well as hub genes obtained from protein-protein interaction (PPI) network analysis using the STRING v10 database. Our analysis focused on the PAEP and PZP genes, whose protein expressions were downregulated in samples with HIF-2α missense mutation. The hub genes of PAEP and PZP were identified using PPI network analysis. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that PAEP and its hub genes were highly enriched in the TGF-β pathway, which is consistent with the analysis of PZP.
Conclusion
Our study proved that the missense mutation of HIF-2α induces the upregulation of PAEP, which is positively related to the poor prognosis of patients with HCC, as it may upregulate the TGF-β pathway. In contrast, PZP downregulation showed the opposite phenomenon, as it may downregulate the TGF-β pathway.
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Affiliation(s)
- Jun Li
- Emergency Department, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Yibo Yan
- Division of Cardiology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
| | - Ganxin Wang
- Division of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zaozao Huang
- Yangchunhu Community Hospital, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
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16
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Wang Y, Liu X, Huang W, Liang J, Chen Y. The intricate interplay between HIFs, ROS, and the ubiquitin system in the tumor hypoxic microenvironment. Pharmacol Ther 2022; 240:108303. [PMID: 36328089 DOI: 10.1016/j.pharmthera.2022.108303] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/16/2022] [Accepted: 10/26/2022] [Indexed: 11/09/2022]
Abstract
Alterations in protein ubiquitination and hypoxia-inducible factor (HIF) signaling both contribute to tumorigenesis and tumor progression. Ubiquitination is a dynamic process that is coordinately regulated by E3 ligases and deubiquitinases (DUBs), which have emerged as attractive therapeutic targets. HIF expression and transcriptional activity are usually increased in tumors, leading to poor clinical outcomes. Reactive oxygen species (ROS) are upregulated in tumors and have multiple effects on HIF signaling and the ubiquitin system. A growing body of evidence has shown that multiple E3 ligases and UBDs function synergistically to control the expression and activity of HIF, thereby allowing cancer cells to cope with the hypoxic microenvironment. Conversely, several E3 ligases and DUBs are regulated by hypoxia and/or HIF signaling. Hypoxia also induces ROS production, which in turn modulates the stability or activity of HIF, E3 ligases, and DUBs. Understanding the complex networks between E3 ligase, DUBs, ROS, and HIF will provide insights into the fundamental mechanism of the cellular response to hypoxia and help identify novel molecular targets for cancer treatment. We review the current knowledge on the comprehensive relationship between E3 ligase, DUBs, ROS, and HIF signaling, with a particular focus on the use of E3 ligase or DUB inhibitors in cancer.
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Affiliation(s)
- Yijie Wang
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China
| | - Xiong Liu
- School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Weixiao Huang
- School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Junjie Liang
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China.
| | - Yan Chen
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China; School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
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17
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Smart chlorotoxin-functionalized liposomes for sunitinib targeted delivery into glioblastoma cells. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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18
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Xu YR, Wang AL, Li YQ. Hypoxia-inducible factor 1-alpha is a driving mechanism linking chronic obstructive pulmonary disease to lung cancer. Front Oncol 2022; 12:984525. [PMID: 36338690 PMCID: PMC9634253 DOI: 10.3389/fonc.2022.984525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/10/2022] [Indexed: 11/27/2022] Open
Abstract
Patients with chronic obstructive pulmonary disease (COPD), irrespective of their smoking history, are more likely to develop lung cancer than the general population. This is mainly because COPD is characterized by chronic persistent inflammation and hypoxia, which are the risk factors for lung cancer. However, the mechanisms underlying this observation are still unknown. Hypoxia-inducible factor 1-alpha (HIF-1α) plays an important role in the crosstalk that exists between inflammation and hypoxia. Furthermore, HIF-1α is the main regulator of somatic adaptation to hypoxia and is highly expressed in hypoxic environments. In this review, we discuss the molecular aspects of the crosstalk between hypoxia and inflammation, showing that HIF-1α is an important signaling pathway that drives COPD progression to lung cancer. Here, we also provide an overview of HIF-1α and its principal regulatory mechanisms, briefly describe HIF-1α-targeted therapy in lung cancer, and summarize substances that may be used to target HIF-1α at the level of COPD-induced inflammation.
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Affiliation(s)
- Yuan-rui Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
| | - An-long Wang
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
| | - Ya-qing Li
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- *Correspondence: Ya-qing Li,
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Maekawa T, Miyake T, Tani M, Uemoto S. Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment. Front Oncol 2022; 12:981547. [PMID: 36203466 PMCID: PMC9531273 DOI: 10.3389/fonc.2022.981547] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechanisms of ascorbic acid on cancer, including the role of ascorbic acid concentration. In addition, we present future perspectives on the effects of ascorbic acid on cancer cells and the CAF microenvironment. Ascorbic acid has a variety of effects, which contributes to the complexity of these effects. Oral administration of ascorbic acid results in low blood concentrations (<0.2 mM) and acts as a cofactor for antioxidant effects, collagen secretion, and HIFα degradation. In contrast, intravenous treatment achieves large blood concentrations (>1 mM) and has oxidative-promoting actions that exert anticancer effects via reactive oxygen species. Therefore, intravenous administration at high concentrations is required to achieve the desired effects on cancer cells during treatment. Partial data on the effect of ascorbic acid on fibroblasts indicate that it may also modulate collagen secretion in CAFs and impart tumor-suppressive effects. Thus, future studies should verify the effect of ascorbic acid on CAFs. The findings of this review can be used to guide further research and clinical trials.
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Affiliation(s)
- Takeru Maekawa
- Division of Gastrointestinal, Breast, Pediatric, and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Toru Miyake
- Division of Gastrointestinal, Breast, Pediatric, and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
- *Correspondence: Toru Miyake,
| | - Masaji Tani
- Division of Gastrointestinal, Breast, Pediatric, and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
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Kojima J, Ono M, Kuji N, Nishi H. Human Chorionic Villous Differentiation and Placental Development. Int J Mol Sci 2022; 23:8003. [PMID: 35887349 PMCID: PMC9325306 DOI: 10.3390/ijms23148003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/19/2022] [Accepted: 07/19/2022] [Indexed: 02/04/2023] Open
Abstract
In humans, the placenta provides the only fetomaternal connection and is essential for establishing a pregnancy as well as fetal well-being. Additionally, it allows maternal physiological adaptation and embryonic immunological acceptance, support, and nutrition. The placenta is derived from extra-embryonic tissues that develop rapidly and dynamically in the first weeks of pregnancy. It is primarily composed of trophoblasts that differentiate into villi, stromal cells, macrophages, and fetal endothelial cells (FEC). Placental differentiation may be closely related to perinatal diseases, including fetal growth retardation (FGR) and hypertensive disorders of pregnancy (HDP), and miscarriage. There are limited findings regarding human chorionic villous differentiation and placental development because conducting in vivo studies is extremely difficult. Placental tissue varies widely among species. Thus, experimental animal findings are difficult to apply to humans. Early villous differentiation is difficult to study due to the small tissue size; however, a detailed analysis can potentially elucidate perinatal disease causes or help develop novel therapies. Artificial induction of early villous differentiation using human embryonic stem (ES) cells/induced pluripotent stem (iPS) cells was attempted, producing normally differentiated villi that can be used for interventional/invasive research. Here, we summarized and correlated early villous differentiation findings and discussed clinical diseases.
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Affiliation(s)
| | - Masanori Ono
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan; (J.K.); (N.K.); (H.N.)
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21
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Mudassar F, Shen H, Cook KM, Hau E. Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment. J Med Imaging Radiat Oncol 2022; 66:560-574. [PMID: 35466515 PMCID: PMC9322583 DOI: 10.1111/1754-9485.13416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 04/05/2022] [Accepted: 04/10/2022] [Indexed: 11/28/2022]
Abstract
Immune checkpoint inhibition with PD‐1/PD‐L1 blockade is a promising area in the field of anti‐cancer therapy. Although clinical data have revealed success of PD‐1/PD‐L1 blockade as monotherapy or in combination with CTLA‐4 or chemotherapy, the combination with radiotherapy could further boost anti‐tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD‐1/PD‐L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD‐1/PD‐L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD‐1/PD‐L1 blockade and radiotherapy.
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Affiliation(s)
- Faiqa Mudassar
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
| | - Han Shen
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
| | - Kristina M Cook
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
- Charles Perkins Centre The University of Sydney Sydney New South Wales Australia
| | - Eric Hau
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
- Department of Radiation Oncology, Crown Princess Mary Cancer Centre Westmead Hospital Sydney New South Wales Australia
- Blacktown Hematology and Cancer Centre Blacktown Hospital Sydney New South Wales Australia
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22
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Li RU, Tang K, Li Q. Pan-cancer Bioinformatics Analysis of the Double-edged Role of Hypoxia-inducible Factor 1α (HIF-1α) in Human Cancer. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:263-278. [PMID: 35399173 PMCID: PMC8962818 DOI: 10.21873/cdp.10104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 01/26/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM Despite the emergence of cellular, animal, and clinical-based evidence demonstrating a link between hypoxia-inducible factor-1α (HIF-1α) and malignancy, the comprehensive assessment of HIF-1α in pan-cancer patients remains unclear, particularly regarding HIF-1α expression and its association with immune infiltration and immune checkpoint. The present study aimed to investigate the role of HIF-1α expression in various types of malignancies through bioinformatics analysis. MATERIALS AND METHODS We investigated the expression and prognostic value of HIF-1α in pan-cancer based on the TCGA (The Cancer Genome Atlas) dataset. The abundance of immune infiltration was estimated by xCell immune deconvolution methods. We investigated the relationship of HIF-1α expression with immune infiltration and immune checkpoint gene expression, with a focus on gastric adenocarcinoma (STAD) and lung squamous cell carcinoma (LUSC). RESULTS HIF-1α expression had different effects on the prognosis of various cancers. In contrast to the protective effect of HIF-1α expression in LUSC, high levels of HIF-1α expression played a detrimental role in the survival of STAD patients. There was a significant positive correlation between HIF-1α expression and immune infiltration in STAD patients, including regulatory T-cells (Tregs), T-cell CD4+ Th2, neutrophils, M1 and M2 macrophages. In addition, immune checkpoint molecules showed different HIF-1α-related profiles in various carcinomas. CONCLUSION A relatively comprehensive view of the oncogenic role of HIF-1α in various tumors based on a pan-cancer analysis is provided in this study. HIF-1α may be considered a poor prognostic biomarker for STAD and, moreover, it may be involved in regulating tumor immune infiltration.
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Affiliation(s)
- R U Li
- Department of Geriatrics, the Hengshui Harrison International Peace Hospital, Hebei, P.R. China
| | - Kang Tang
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Qian Li
- Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
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23
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Zhang A, Huang Z, Tao W, Zhai K, Wu Q, Rich JN, Zhou W, Bao S. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. EMBO J 2022; 41:e109187. [PMID: 35191554 PMCID: PMC8982626 DOI: 10.15252/embj.2021109187] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/17/2022] Open
Abstract
Hypoxia regulates tumor angiogenesis, metabolism, and therapeutic response in malignant cancers including glioblastoma, the most lethal primary brain tumor. The regulation of HIF transcriptional factors by the ubiquitin-proteasome system is critical in the hypoxia response, but hypoxia-inducible deubiquitinases that counteract the ubiquitination remain poorly defined. While the activation of ERK1/2 also plays an important role in hypoxia response, the relationship between ERK1/2 activation and HIF regulation remains elusive. Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. USP33 is preferentially induced in glioma stem cells by hypoxia and interacts with HIF-2alpha, leading to its stabilization through deubiquitination. The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33. Silencing of USP33 disrupted glioma stem cells maintenance, reduced tumor vascularization, and inhibited glioblastoma growth. Our findings highlight USP33 as an essential regulator of hypoxia response in cancer stem cells, indicating a novel potential therapeutic target for brain tumor treatment.
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Affiliation(s)
- Aili Zhang
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Zhi Huang
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Weiwei Tao
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Kui Zhai
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Qiulian Wu
- Hillman Cancer CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA
| | - Jeremy N Rich
- Hillman Cancer CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA
| | - Wenchao Zhou
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Shideng Bao
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA,Case Comprehensive Cancer CenterCase Western Reserve University School of MedicineClevelandOHUSA,Center for Cancer Stem Cell ResearchLerner Research InstituteCleveland ClinicClevelandOHUSA
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24
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Understanding the Critical Role of Glycolysis-Related lncRNAs in Lung Adenocarcinoma Based on Three Molecular Subtypes. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7587398. [PMID: 35178454 PMCID: PMC8845143 DOI: 10.1155/2022/7587398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/21/2021] [Accepted: 12/28/2021] [Indexed: 12/18/2022]
Abstract
Background Glycolysis is closely associated with tumor progression, but the roles of lncRNAs in glycolysis have not been comprehensively investigated in lung adenocarcinoma (LUAD). This study is aimed at studying the possible mechanisms of glycolysis-related lncRNAs in tumor development and providing a guidance for targeted therapy. Methods Unsupervised consensus clustering was used to identify molecular subtypes. Gene enrichment analysis was applied to screen important pathways involved in tumor progression. A series of immune analysis was performed to assess immune infiltration. Critical transcription factors (TFs) interacting with lncRNAs were selected by Pearson correlation analysis. A first-order partial correlation analysis was implemented to identify critical lncRNAs with prognostic significance. Results Three molecular subtypes (C1, C2, and C3) were identified with distinct overall survival. Three subtypes showed differential immune infiltration, and C3 subtype was the optimal for immunotherapy treatment. Ten lncRNA-TF pairs among four glycolysis-related lncRNAs (FTX, LINC00472, PSMA3-AS1, and SNHG14) and six TFs (FOXP1, SP1, MYC, FOXM1, HIF1A, and FOS) were involved in tumor progression. We identified four critical glycolysis-related lncRNAs significantly associated with prognosis. Conclusions This study identified three molecular subtypes that could guide personalized therapy. The four-lncRNA prognostic model can serve as an indicator for predicting prognosis or early screening of lung adenocarcinoma patients. The current results improve the understanding of the relation between lncRNAs and glycolysis.
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Chipurupalli S, Desiderio V, Robinson N. Analysis of ER-Phagy in Cancer Drug Resistance. Methods Mol Biol 2022; 2535:211-220. [PMID: 35867233 DOI: 10.1007/978-1-0716-2513-2_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The ability of the cancer cells to survive hostile environment depends on their cellular stress response mechanisms. These mechanisms also help them to develop resistance to chemotherapies. Autophagy and more specifically organelle specific autophagy is one such adaptive mechanism that promotes drug resistance in cancer cells. Endoplasmic reticulum-specific autophagy or ER-phagy has been more recently described to overcome ER-stress through the degradation of damaged ER. ER-resident proteins such as FAM134B act as ER-phagy receptors to specifically target damaged ER for degradation through autophagy. Moreover, we had recently deciphered that ER-phagy facilitates cancer cell survival during hypoxic stress and we predict that this process could play a critical role in the development of drug resistance in cancer cells. Therefore, here, we provide a lay description of how ER-phagy could be investigated biochemically by Western blot analysis and silencing ER-phagy receptor genes using small interfering RNAs (siRNA).
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Affiliation(s)
- Sandhya Chipurupalli
- Cellular Stress and Immune Response Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Departments of Pediatrics & Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, NS, Canada
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Nirmal Robinson
- Cellular Stress and Immune Response Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
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Iessi E, Vona R, Cittadini C, Matarrese P. Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path. Biomedicines 2021; 9:biomedicines9121942. [PMID: 34944758 PMCID: PMC8698563 DOI: 10.3390/biomedicines9121942] [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: 11/15/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.
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27
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Carvalho TMA, Di Molfetta D, Greco MR, Koltai T, Alfarouk KO, Reshkin SJ, Cardone RA. Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches. Cancers (Basel) 2021; 13:6135. [PMID: 34885243 PMCID: PMC8657427 DOI: 10.3390/cancers13236135] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/14/2022] Open
Abstract
Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.
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Affiliation(s)
- Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | | | - Khalid O. Alfarouk
- Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munwarah 42316, Saudi Arabia;
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Rosa A. Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
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El-Houjeiri L, Biondini M, Paquette M, Kuasne H, Pacis A, Park M, Siegel PM, Pause A. Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis. J Clin Invest 2021; 131:144871. [PMID: 34779410 DOI: 10.1172/jci144871] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 09/21/2021] [Indexed: 12/13/2022] Open
Abstract
Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
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Affiliation(s)
| | | | | | | | | | - Morag Park
- Goodman Cancer Institute.,Department of Biochemistry.,Department of Medicine, and.,Department of Pathology, McGill University, Montréal, Canada
| | - Peter M Siegel
- Goodman Cancer Institute.,Department of Biochemistry.,Department of Medicine, and
| | - Arnim Pause
- Goodman Cancer Institute.,Department of Biochemistry
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29
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Pons-Tostivint E, Lugat A, Fontenau JF, Denis MG, Bennouna J. STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact. Cells 2021; 10:cells10113129. [PMID: 34831355 PMCID: PMC8618117 DOI: 10.3390/cells10113129] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/28/2021] [Accepted: 11/09/2021] [Indexed: 12/20/2022] Open
Abstract
The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.
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Affiliation(s)
- Elvire Pons-Tostivint
- Medical Oncology Department, Nantes University Hospital, 44000 Nantes, France
- Center for Research in Cancerology and Immunology Nantes-Angers (CRCINA), University of Nantes, INSERM UMR 1232, 44000 Nantes, France; (A.L.); (J.-F.F.); (J.B.)
- Correspondence:
| | - Alexandre Lugat
- Center for Research in Cancerology and Immunology Nantes-Angers (CRCINA), University of Nantes, INSERM UMR 1232, 44000 Nantes, France; (A.L.); (J.-F.F.); (J.B.)
| | - Jean-François Fontenau
- Center for Research in Cancerology and Immunology Nantes-Angers (CRCINA), University of Nantes, INSERM UMR 1232, 44000 Nantes, France; (A.L.); (J.-F.F.); (J.B.)
| | | | - Jaafar Bennouna
- Center for Research in Cancerology and Immunology Nantes-Angers (CRCINA), University of Nantes, INSERM UMR 1232, 44000 Nantes, France; (A.L.); (J.-F.F.); (J.B.)
- Medical Oncology Department, Hopital Foch, 75073 Suresnes, France
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Bisht VS, Giri K, Kumar D, Ambatipudi K. Oxygen and metabolic reprogramming in the tumor microenvironment influences metastasis homing. Cancer Biol Ther 2021; 22:493-512. [PMID: 34696706 DOI: 10.1080/15384047.2021.1992233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Tumor metastasis is the leading cause of cancer mortality, often characterized by abnormal cell growth and invasion to distant organs. The cancer invasion due to epithelial to mesenchymal transition is affected by metabolic and oxygen availability in the tumor-associated micro-environment. A precise alteration in oxygen and metabolic signaling between healthy and metastatic cells is a substantial probe for understanding tumor progression and metastasis. Molecular heterogeneity in the tumor microenvironment help to sustain the metastatic cell growth during their survival shift from low to high metabolic-oxygen-rich sites and reinforces the metastatic events. This review highlighted the crucial role of oxygen and metabolites in metastatic progression and exemplified the role of metabolic rewiring and oxygen availability in cancer cell adaptation. Furthermore, we have also addressed potential applications of altered oxygen and metabolic networking with tumor type that could be a signature pattern to assess tumor growth and chemotherapeutics efficacy in managing cancer metastasis.
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Affiliation(s)
- Vinod S Bisht
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India
| | - Kuldeep Giri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India
| | - Deepak Kumar
- Department of Cancer Biology, Central Drug Research Institute, Lucknow, India.,Academy of Scientific & Innovative Research, New Delhi, India
| | - Kiran Ambatipudi
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India
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Bastani S, Akbarzadeh M, Rastgar Rezaei Y, Farzane A, Nouri M, Mollapour Sisakht M, Fattahi A, Akbarzadeh M, Reiter RJ. Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved. Int J Mol Sci 2021; 22:10874. [PMID: 34639215 PMCID: PMC8509383 DOI: 10.3390/ijms221910874] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 12/27/2022] Open
Abstract
Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.
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Affiliation(s)
- Sepideh Bastani
- Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz 51368, Iran;
- Stem Cell And Regenerative Medicine Institute (SCARM), Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Moloud Akbarzadeh
- Stem Cell And Regenerative Medicine Institute (SCARM), Tabriz University of Medical Sciences, Tabriz 51368, Iran;
- Department of Cellular and Molecular Biology, Faculty of Biological Science, Azarbaijan Shahid Madani University, Tabriz 51368, Iran
| | - Yeganeh Rastgar Rezaei
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Ali Farzane
- Department of Health Information Management, School of Allied Medical Science, Tehran University of Medical Sciences, Tehran 11369, Iran;
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Mahsa Mollapour Sisakht
- Stem Cell and Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran 11369, Iran;
- Department of Biochemistry, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - Amir Fattahi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
- Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander University of Erlangen–Nürnberg, Comprehensive Cancer Center ER-EMN, 91054 Erlangen, Germany
| | - Maryam Akbarzadeh
- Department of Biochemistry, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health, Long School of Medicine, San Antonio, TX 78229, USA;
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Shaik S, Maegawa S, Gopalakrishnan V. Medulloblastoma: novel insights into emerging therapeutic targets. Expert Opin Ther Targets 2021; 25:615-619. [PMID: 34602009 DOI: 10.1080/14728222.2021.1982896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Shavali Shaik
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shinji Maegawa
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vidya Gopalakrishnan
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Dzhalilova DS, Makarova OV. HIF-Dependent Mechanisms of Relationship between Hypoxia Tolerance and Tumor Development. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:1163-1180. [PMID: 34903150 DOI: 10.1134/s0006297921100011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Oxygen deficiency is one of the key pathogenetic factors determining development and severity of many diseases, including inflammatory, infectious diseases, and cancer. Lack of oxygen activates the signaling pathway of the hypoxia-inducible transcription factor HIF in cells that has three isoforms, HIF-1, HIF-2, HIF-3, regulating expression of several thousand genes. Throughout tumor progression, HIF activation stimulates angiogenesis, promotes changes in cell metabolism, adhesion, invasiveness, and ability to metastasize. HIF isoforms can play opposite roles in the development of inflammatory and neoplastic processes. Humans and laboratory animals differ both in tolerance to hypoxia and in the levels of expression of HIF and HIF-dependent genes, which may lead to predisposition to the development of certain oncological disorders. In particular, the ratio of different histogenetic types of tumors may vary among people living in the mountains and at the sea level. However, despite the key role of hypoxia at almost all stages of tumor development, basal tolerance to oxygen deficiency is not considered as a factor of predisposition to the tumor growth initiation. In literature, there are many works characterizing the level of local hypoxia in various tumors, and suggesting fundamental approaches to its mitigation by HIF inhibition. HIF inhibitors, as a rule, have a systemic effect on the organism, however, basal tolerance of an organism to hypoxia as well as the level of HIF expression are not taken into account in the process of their use. The review summarizes the literature data on different HIF isoforms and their role in tumor progression, with extrapolation to organisms with high and low tolerance to hypoxia, as well as on the prevalence of various types of tumors in the populations living at high altitudes.
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Affiliation(s)
- Dzhuliia Sh Dzhalilova
- Federal State Budgetary Institution "Research Institute of Human Morphology", Moscow, 117418, Russia.
| | - Olga V Makarova
- Federal State Budgetary Institution "Research Institute of Human Morphology", Moscow, 117418, Russia
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Romero Y, Aquino-Gálvez A. Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution. Int J Mol Sci 2021; 22:8335. [PMID: 34361103 PMCID: PMC8348404 DOI: 10.3390/ijms22158335] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/16/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022] Open
Abstract
Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the activation of the hypoxia response, promoting cell survival even during chronic conditions. The role of hypoxia-inducible factors (HIFs) as master regulators of this adaptation is crucial in both lung cancer and idiopathic pulmonary fibrosis, which have shown the active transcriptional signature of this pathway. Emerging evidence suggests that interconnected feedback loops such as metabolic changes, fibroblast differentiation or extracellular matrix remodeling contribute to HIF overactivation, making it an irreversible phenomenon. This review will focus on the role of HIF signaling and its possible overlapping in order to identify new opportunities in therapy and regeneration.
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Affiliation(s)
- Yair Romero
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Arnoldo Aquino-Gálvez
- Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Mexico City 14080, Mexico
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Kaymak ZA, Karahan N, Erdoğan M, Erdemoğlu E, Zihni İ, Şengül SS. Correlation of 18F-FDG/PET SUV max, SUV mean, MTV, and TLG with HIF-1α in Patients with Colorectal Cancer. Mol Imaging Radionucl Ther 2021; 30:93-100. [PMID: 34082509 PMCID: PMC8185477 DOI: 10.4274/mirt.galenos.2021.04934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Objectives: Post-hypoxia hypoxia-inducible factor (HIF)-1α activation plays a vital role in colorectal cancer (CRC) angiogenesis. Although glucose metabolism is induced in some cancer types via HIF-1α, the prognostic significance of HIF-1α in CRC and its correlation with 18fluorinefluorodeoxyglucose (18F-FDG) uptake in positron emission tomography (PET) remain controversial. This study aims to investigate the association between 18F-FDG/PET parameters and HIF-1α expression in CRC. Methods: Thirty-six histopathologically confirmed patients with CRC who had 18F-FDG/PET scans before surgery were enrolled in the study. The correlations between the maximum standardized uptake value (SUVmax), SUVmean, metabolic tumor volume (MTV), total lesion glycolysis, HIF-1α overexpression, and histopathological features were evaluated. Results: The tumor location, tumor diameter, perineural invasion, lymphovascular invasion, T and N stage were not significantly correlated with HIF-1α overexpression. In contrast, the tumor differentiation was negatively correlated with HIF-1α expression (r=-0.332, p=0.048). None of the 18F-FDG/PET parameters was significantly correlated with HIF-1α overexpression. A significant relationship was found between tumor differentiation, tumor necrosis percentage, and MTV (p=0.030, p=0.020). Conclusion: The expected association between HIF-1α overexpression and 18F-FDG/PET parameters was not found in this study. However, there was a relationship between MTV, tumor differentiation, and tumor necrosis percentage. Hence, further studies are required to predict the pathological and prognostic courses of CRC using a diagnostic 18F-FDG/PET evaluation.
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Affiliation(s)
- Zümrüt Arda Kaymak
- Süleyman Demirel University Faculty of Medicine, Department of Radiaiton Oncology, Isparta, Turkey
| | - Nermin Karahan
- Süleyman Demirel University Faculty of Medicine, Department of Pathology, Isparta, Turkey
| | - Mehmet Erdoğan
- Süleyman Demirel University Faculty of Medicine, Department of Nuclear Medicine, Isparta, Turkey
| | - Evrim Erdemoğlu
- Süleyman Demirel University Faculty of Medicine, Department of Gynecologic Oncology, Isparta, Turkey
| | - İsmail Zihni
- Süleyman Demirel University Faculty of Medicine, Department of Surgical Oncology, Isparta, Turkey
| | - Sevim Süreyya Şengül
- Süleyman Demirel University Faculty of Medicine, Department of Nuclear Medicine, Isparta, Turkey
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Ding ZN, Dong ZR, Chen ZQ, Yang YF, Yan LJ, Li HC, Liu KX, Yao CY, Yan YC, Yang CC, Li T. Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: A systematic review with meta-analysis. J Gastroenterol Hepatol 2021; 36:1487-1496. [PMID: 33393670 DOI: 10.1111/jgh.15395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 12/08/2020] [Accepted: 12/28/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.
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Affiliation(s)
- Zi-Niu Ding
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Ya-Fei Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Hai-Chao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Kai-Xuan Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Cheng-Yu Yao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Chun-Cheng Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
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Li X, Wang M, Li S, Chen Y, Wang M, Wu Z, Sun X, Yao L, Dong H, Song Y, Xu Y. HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia. Am J Cancer Res 2021; 11:7337-7359. [PMID: 34158854 PMCID: PMC8210597 DOI: 10.7150/thno.57804] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/16/2021] [Indexed: 01/16/2023] Open
Abstract
Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.
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Koren A, Rijavec M, Krumpestar T, Kern I, Sadikov A, Čufer T, Korošec P. Gene Expression Levels of the Prolyl Hydroxylase Domain Proteins PHD1 and PHD2 but Not PHD3 Are Decreased in Primary Tumours and Correlate with Poor Prognosis of Patients with Surgically Resected Non-Small-Cell Lung Cancer. Cancers (Basel) 2021; 13:cancers13102309. [PMID: 34065840 PMCID: PMC8150639 DOI: 10.3390/cancers13102309] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) belong to an evolutionarily conserved superfamily of dioxygenases that play a role in cell oxygen sensing and homeostasis. In this study, we evaluated PHD1, PHD2 and PHD3 mRNA expression in 60 NSCLC tumours and compared it to that in normal lungs and evaluated the prognostic significance of these differences for distinguishing the survival of NSCLC patients treated with radical surgery. Our results showed that the mRNA expression PHD1 and PHD2 in NSCLC primary tumours was decreased, which correlated with larger tumour size and poor prognosis of patients. PHD1 also showed borderline independent prognostic value in multivariate analysis. In contrast, we found no associations between PHD3 expression and any of the observed parameters. Our results suggest that loss of PHD1 and PHD2 expression is associated with the development and progression of NSCLC, whereas PHD1 could be further assessed as a prognostic marker in NSCLC. Abstract Background: Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) play a role in cell oxygen sensing, negatively regulating the hypoxia-inducible factor (HIF) pathway. Our study aim was to evaluate PHD1, PHD2 and PHD3 mRNA expression levels in primary tumours and normal lungs of non-small-cell lung cancer (NSCLC) patients and to correlate it with selected regulators of HIF signalling, with clinicopathological characteristics and overall survival (OS). Methods: Tumour tissue samples were obtained from 60 patients with surgically resected NSCLC who were treated with radical surgery. In 22 out of 60 cases, matching morphologically normal lung tissue was obtained. PHD1, PHD2 and PHD3 mRNA expressions were measured using RT-qPCR. Results: The PHD1 and PHD2 mRNA levels in primary tumours were significantly decreased compared to those in normal lungs (both p < 0.0001). PHD1 and PHD2 expression in tumours was positively correlated (rs = 0.82; p < 0.0001) and correlated well with HIF pathway downstream genes HIF1A, PKM2 and PDK1. Decreased PHD1 and PHD2 were associated with larger tumour size, higher tumour stage (PHD1 only) and squamous cell carcinoma. Patients with low PHD1 and patients with low PHD2 expression had shorter OS than patients with high PHD1 (p = 0.02) and PHD2 expression (p = 0.01). PHD1 showed borderline independent prognostic values in multivariate analysis (p = 0.06). In contrast, we found no associations between PHD3 expression and any of the observed parameters. Conclusions: Our results show that reduced expression of PHD1 and PHD2 is associated with the development and progression of NSCLC. PHD1 could be further assessed as a prognostic marker in NSCLC.
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Affiliation(s)
- Ana Koren
- University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; (M.R.); (T.K.); (I.K.); (T.Č.); (P.K.)
- Correspondence: ; Tel.: +386-(0)4-25-69-433
| | - Matija Rijavec
- University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; (M.R.); (T.K.); (I.K.); (T.Č.); (P.K.)
| | - Tomaž Krumpestar
- University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; (M.R.); (T.K.); (I.K.); (T.Č.); (P.K.)
| | - Izidor Kern
- University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; (M.R.); (T.K.); (I.K.); (T.Č.); (P.K.)
| | - Aleksander Sadikov
- Faculty of Computer and Information Science, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Tanja Čufer
- University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; (M.R.); (T.K.); (I.K.); (T.Č.); (P.K.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Peter Korošec
- University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; (M.R.); (T.K.); (I.K.); (T.Č.); (P.K.)
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Datta KK, Periasamy P, Mohan SV, Ziegman R, Gowda H. Temporal Quantitative Proteomics Reveals Proteomic and Phosphoproteomic Alterations Associated with Adaptive Response to Hypoxia in Melanoma Cells. Cancers (Basel) 2021; 13:cancers13092175. [PMID: 33946525 PMCID: PMC8124723 DOI: 10.3390/cancers13092175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Most solid tumours, including melanoma (skin cancer), are riddled with areas lacking adequate oxygen supply due to insufficient vasculature. Cancer cells in these regions are resistant to therapies and contribute to cancer spread and poor treatment response in patients. Understanding the mechanisms by which cancer cells adapt to survive in such a hostile environment will provide novel avenues for treatment. In this study, we investigated mechanisms that melanoma cells use to adapt and survive in an oxygen-poor environment. We used four different melanoma cell lines and studied how protein levels and phosphorylation patterns on thousands of proteins change when the cells are exposed to poor oxygen conditions. This revealed potential mechanisms on which cancer cells are dependent for survival. These survival mechanisms can be potentially targeted to achieve durable response to therapy. We demonstrate this by targeting one such mechanism required for cancer cell survival. Abstract Hypoxia is a common feature in various solid tumours, including melanoma. Cancer cells in hypoxic environments are resistant to both chemotherapy and radiation. Hypoxia is also associated with immune suppression. Identification of proteins and pathways that regulate cancer cell survival in hypoxic environments can reveal potential vulnerabilities that can be exploited to improve the efficacy of anticancer therapies. We carried out temporal proteomic and phosphoproteomic profiling in melanoma cell lines to identify hypoxia-induced protein expression and phosphorylation changes. By employing a TMT-based quantitative proteomics strategy, we report the identification and quantitation of >7000 proteins and >10,000 phosphosites in melanoma cell lines grown in hypoxia. Proteomics data show metabolic reprogramming as one of the prominent adaptive responses in hypoxia. We identify several novel hypoxia-mediated phosphorylation changes that have not been reported before. They reveal kinase signalling pathways that are potentially involved in modulating cellular response to hypoxia. In addition to known protein expression changes, we identify several novel proteomic alterations associated with adaptive response to hypoxia. We show that cancer cells require the ubiquitin–proteasome system to survive in both normoxia and hypoxia. Inhibition of proteasome activity affects cell survival and may provide a novel therapeutic avenue to target cancer cells in hypoxia. Our study can serve as a valuable resource to pursue novel candidates to target hypoxia in cancers and improve the efficacy of anticancer therapies.
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Affiliation(s)
- Keshava K. Datta
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (P.P.); (S.V.M.); (R.Z.)
- Correspondence: (K.K.D.); (H.G.)
| | - Parthiban Periasamy
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (P.P.); (S.V.M.); (R.Z.)
- Faculty of Medicine, University of Queensland, Brisbane, QLD 4006, Australia
| | - Sonali V. Mohan
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (P.P.); (S.V.M.); (R.Z.)
- Faculty of Medicine, University of Queensland, Brisbane, QLD 4006, Australia
| | - Rebekah Ziegman
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (P.P.); (S.V.M.); (R.Z.)
| | - Harsha Gowda
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (P.P.); (S.V.M.); (R.Z.)
- Faculty of Medicine, University of Queensland, Brisbane, QLD 4006, Australia
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4006, Australia
- Correspondence: (K.K.D.); (H.G.)
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Uncovering the Anti-Lung-Cancer Mechanisms of the Herbal Drug FDY2004 by Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6644018. [PMID: 33628308 PMCID: PMC7886515 DOI: 10.1155/2021/6644018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/21/2021] [Accepted: 01/28/2021] [Indexed: 12/24/2022]
Abstract
With growing evidence on the therapeutic efficacy and safety of herbal drugs, there has been a substantial increase in their application in the lung cancer treatment. Meanwhile, their action mechanisms at the system level have not been comprehensively uncovered. To this end, we employed a network pharmacology methodology to elucidate the systematic action mechanisms of FDY2004, an anticancer herbal drug composed of Moutan Radicis Cortex, Persicae Semen, and Rhei Radix et Rhizoma, in lung cancer treatment. By evaluating the pharmacokinetic properties of the chemical compounds present in FDY2004 using herbal medicine-associated databases, we identified its 29 active chemical components interacting with 141 lung cancer-associated therapeutic targets in humans. The functional enrichment analysis of the lung cancer-related targets of FDY2004 revealed the enriched Gene Ontology terms, involving the regulation of cell proliferation and growth, cell survival and death, and oxidative stress responses. Moreover, we identified key FDY2004-targeted oncogenic and tumor-suppressive pathways associated with lung cancer, including the phosphatidylinositol 3-kinase-Akt, mitogen-activated protein kinase, tumor necrosis factor, Ras, focal adhesion, and hypoxia-inducible factor-1 signaling pathways. Overall, our study provides novel evidence and basis for research on the comprehensive anticancer mechanisms of herbal medicines in lung cancer treatment.
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Yang Y, Liu L, Sun J, Wang S, Yang Z, Li H, Huang N, Zhao W. Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis. Front Oncol 2021; 11:629543. [PMID: 33732648 PMCID: PMC7959795 DOI: 10.3389/fonc.2021.629543] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/11/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer cell proliferation is a metabolically demanding process that requires high rate of glycolysis to support anabolic growth. Deoxypodophyllotoxin (DPT) is a natural flavonolignan with various pharmacological activities, including antitumor effect. However, whether DPT affects the metabolic reprogramming of cancer cells is unknown. The purpose of this study is to investigate the role of DPT on non-small cell lung cancer (NSCLC) and to explore whether HIF-1α-mediated glycolysis is involved in its mechanism of action.The level of HIF-1α mRNA and protein in NSCLC cells following DPT treatment was detected using qRT-PCR and western blotting, respectively. Cell Counting Kit-8 (CCK-8) and caspase-3 activity assays were performed to analyze cell proliferation and apoptosis. The underlying molecular mechanism was identified by dual luciferase assay, Western blotting, qRT-PCR, glucose consumption, lactate production, and immunoprecipitation. A murine NSCLC model was used to clarify the effect of DPT treatment on tumor cell proliferation. Our findings showed that DPT treatment inhibited NSCLC cell growth in a dose- and time-dependent manner. Further analysis suggested that DPT treatment inhibited HIF-1α signaling pathway by Parkin-mediated protein degradation in NSCLC cells. DPT treatment significantly decreased glucose consumption and lactate production. In addition, DPT treatment reduced the expression of HIF-1α target genes, including GLUT1, HK2 and LDHA, resulting in reduction in glycolysis. We further revealed that DPT-induced cell growth inhibition and increased glucose and lactate levels could be reversed by overexpressing HIF-1α. Additionally, we found that DPT repressed NSCLC growth and GLUT1, HK2 and LDHA expression in vivo. Overall, this study suggested that DPT inhibited NSCLC growth by preventing HIF-1α-mediated glycolysis.
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Affiliation(s)
- Yuping Yang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Lingling Liu
- School of Laboratory Medicine/Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu Medical College, Chengdu, China
- Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China
| | - Jinghui Sun
- School of Laboratory Medicine/Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu Medical College, Chengdu, China
| | - Shu Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
| | | | - Honghui Li
- Department of Refractive Surgery, Chengdu Aier Eye Hospital, Chengdu, China
| | - Na Huang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Wei Zhao
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- School of Laboratory Medicine/Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu Medical College, Chengdu, China
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Role of Central Hypo-enhancement in the Hepatic Arterial Phase of Dynamic Computed Tomography in Patients with Mass-Forming Intrahepatic Cholangiocarcinoma. World J Surg 2021; 44:2350-2358. [PMID: 32152739 DOI: 10.1007/s00268-020-05456-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND/PURPOSE The enhancement pattern in the hepatic arterial phase (HAP) of dynamic computed tomography (CT) is reportedly a prognostic marker in patients with intrahepatic cholangiocarcinoma (IHCC). This study was performed to clarify the significance of central hypo-enhancement in the HAP in patients with mass-forming IHCC. METHODS Forty patients who had undergone initial surgical resection for mass-forming IHCC were enrolled. The dynamic CT was scanned 40 s after contrast agent injection as the HAP. A radiologist classified the patients into three groups based on the vascular pattern: the hyper-enhancement group (Hyper group), rim-enhancement group (Rim group), and hypo-enhancement group (Hypo group). The surgical specimens were immunohistochemically stained for hypoxia-inducible factor 1 (HIF-1). The correlation with clinicopathological findings and HIF-1 expression was investigated. RESULTS The Hyper, Rim, and Hypo groups comprised 8, 7, and 25 patients, respectively. There were no significant correlations between the groups and clinicopathological factors. Overall survival (OS) was significantly worse in the Hypo than in the Hyper group (p = 0.03). OS was also significantly worse in the Rim + Hypo group (i.e., hypo-enhancement in the central tumor) than in the Hyper group (p = 0.04). Furthermore, inclusion in the Rim + Hypo group was a prognostic factor for OS (hazard ratio 6.68). High HIF-1 expression in the central part of the tumor was correlated with central hypo-enhancement (Hyper group: 25% and Rim + Hypo group: 72%). CONCLUSIONS Central hypo-enhancement was a prognostic factor in patients with IHCC. The high malignant potential of tumors with central hypo-enhancement might be associated with HIF-1 upregulation.
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Ziółkowska-Suchanek I. Mimicking Tumor Hypoxia in Non-Small Cell Lung Cancer Employing Three-Dimensional In Vitro Models. Cells 2021; 10:cells10010141. [PMID: 33445709 PMCID: PMC7828188 DOI: 10.3390/cells10010141] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in the field of tumor hypoxia in non-small cell lung cancer (NSCLC), including biology, biomarkers, in vitro and in vivo studies and also hypoxia imaging and detection. While classic two-dimensional (2D) in vitro research models reveal some hypoxia dependent manifestations, three-dimensional (3D) cell culture models more accurately replicate the hypoxic TME. In this study, a systematic review of the current NSCLC 3D models that have been able to mimic the hypoxic TME is presented. The multicellular tumor spheroid, organoids, scaffolds, microfluidic devices and 3D bioprinting currently being utilized in NSCLC hypoxia studies are reviewed. Additionally, the utilization of 3D in vitro models for exploring biological and therapeutic parameters in the future is described.
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Sun J, Xiong Y, Jiang K, Xin B, Jiang T, Wei R, Zou Y, Tan H, Jiang T, Yang A, Jia L, Wang L. Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis. J Exp Clin Cancer Res 2021; 40:12. [PMID: 33407675 PMCID: PMC7789733 DOI: 10.1186/s13046-020-01806-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive. METHODS Firstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples. RESULTS CASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients. CONCLUSIONS HIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC.
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Affiliation(s)
- Jianyong Sun
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Kuo Jiang
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Bo Xin
- Department of Oncology, The 960th Hospital of PLA, Tai'an, 271000, Shandong, China
| | - Tongtong Jiang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Renji Wei
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yuankang Zou
- The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Department of Occupational and Environmental Health, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hong Tan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Angang Yang
- Department of Immunology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Lei Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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Elzakra N, Kim Y. HIF-1α Metabolic Pathways in Human Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1280:243-260. [PMID: 33791987 DOI: 10.1007/978-3-030-51652-9_17] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxygen is directly involved in many key pathophysiological processes. Oxygen deficiency, also known as hypoxia, could have adverse effects on mammalian cells, with ischemia in vital tissues being the most significant (Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 164(6): 1875-1882, 2004); therefore, timely adaptive responses to variations in oxygen availability are essential for cellular homeostasis and survival. The most critical molecular event in hypoxic response is the activation and stabilization of a transcriptional factor termed hypoxia-induced factor-1 (HIF-1) that is responsible for the upregulation of many downstream effector genes, collectively known as hypoxia-responsive genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes; thus, HIF-1-mediated pathways are equally pivotal in both physiology and pathology.As we gain knowledge on the molecular mechanisms underlying the regulation of HIF-1, a great focus has been placed on elucidating the cellular function of HIF-1, particularly the role of HIF-1 in cancer pathogenesis pathways such as proliferation, invasion, angiogenesis, and metastasis. In cancer, HIF-1 is directly involved in the shift of cancer tissues from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. Although targeting HIF-1 as a cancer therapy seems like an extremely rational approach, owing to the complex network of its downstream effector genes, the development of specific HIF-1 inhibitors with fewer side effects and more specificity has not been achieved. Therefore, in this review, we provide a brief background about the function of HIF proteins in hypoxia response with a special emphasis on the unique role played by HIF-1α in cancer growth and invasiveness, in the hypoxia response context.
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Affiliation(s)
- Naseim Elzakra
- School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA.
| | - Yong Kim
- School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA. .,Laboratory of Stem Cell and Cancer Epigenetics, Center for Oral Oncology Research, UCLA School of Dentistry, Los Angeles, CA, USA. .,UCLA's Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. .,Broad Stem Cell Research Institute, Los Angeles, CA, USA.
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Reyes A, Corrales N, Gálvez NMS, Bueno SM, Kalergis AM, González PA. Contribution of hypoxia inducible factor-1 during viral infections. Virulence 2020; 11:1482-1500. [PMID: 33135539 PMCID: PMC7605355 DOI: 10.1080/21505594.2020.1836904] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/15/2020] [Accepted: 10/11/2020] [Indexed: 12/15/2022] Open
Abstract
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays critical roles during the cellular response to hypoxia. Under normoxic conditions, its function is tightly regulated by the degradation of its alpha subunit (HIF-1α), which impairs the formation of an active heterodimer in the nucleus that otherwise regulates the expression of numerous genes. Importantly, HIF-1 participates in both cancer and infectious diseases unveiling new therapeutic targets for those ailments. Here, we discuss aspects related to the activation of HIF-1, the effects of this transcription factor over immune system components, as well as the involvement of HIF-1 activity in response to viral infections in humans. Although HIF-1 is currently being assessed in numerous clinical settings as a potential therapy for different diseases, up to date, there are no clinical studies evaluating the pharmacological modulation of this transcription factor as a possible new antiviral treatment. However, based on the available evidence, clinical trials targeting this molecule are likely to occur soon. In this review we discuss the role of HIF-1 in viral immunity, the modulation of HIF-1 by different types of viruses, as well as the effects of HIF-1 over their life cycle and the potential use of HIF-1 as a new target for the treatment of viral infections.
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Affiliation(s)
- Antonia Reyes
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nicolás Corrales
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nicolás M. S. Gálvez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M. Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento De Endocrinología, Facultad De Medicina, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Zhu P, Shen L, Ren Q, Zeng Q, He X. Prognostic and Clinicopathological Significance of Hypoxia-Inducible Factor-1α in Endometrial Cancer: A Meta-Analysis. Front Oncol 2020; 10:587420. [PMID: 33304847 PMCID: PMC7693720 DOI: 10.3389/fonc.2020.587420] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/22/2020] [Indexed: 12/19/2022] Open
Abstract
Background Current reports on the prognostic and predictive value of hypoxia-inducible factor-1α (HIF-1α) in endometrial carcinoma are inconsistent. Therefore, we conducted this meta-analysis to precisely evaluate the association of HIF-1α expression with susceptibility, clinical features, and prognosis of endometrial cancer. Methods Eligible studies that assessed the role of HIF-1α protein expression, immunohistochemistry detection, disease susceptibility, clinical features, and prognosis of endometrial cancer were searched from the Embase, Pubmed, and Web of Science databases. Stata 14.0 software was used to merge and compute pooled hazard ratios (HR) and odds ratios (OR). Information including HIF-1α protein expression and clinical progression of endometrial cancer was extracted. The pooled HR and OR with corresponding 95% confidence intervals (CI) were used to estimate the strength of these associations. Results A total of 25 studies were included in the analysis. HIF-1α protein expression in endometrial cancer tissue was significantly higher than that in normal tissues (OR = 15.79, 95% CI = 8.44–29.52, P < 0.05). Endometrial cancer patients with higher HIF-1α protein expression had poorer prognosis compared to patients with low HIF-1α protein expression (HR = 2.29, 95% CI = 1.68–2.90, P < 0.05). In addition, high HIF-1α protein expression was significantly associated with endometrial cancer grade, lymph node metastasis, and myometrial invasion (grade in Caucasians: OR = 3.09, 95% CI = 1.63–5.85, P < 0.05; lymph node metastasis: OR = 3.09, 95% CI = 1.63–5.85, P < 0.05; myometrial invasion: OR = 2.26, 95% CI = 2.15–5.08, P < 0.05). Conclusions HIF-1α overexpression was significantly associated with increased risk, advanced clinical progression, and poor prognosis in endometrial cancer patients.
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Affiliation(s)
- Ping Zhu
- Department of Gynaecology and Obstetrics, Heze Municipal Hospital, Heze City, China
| | - Longxia Shen
- Department of Gynaecology and Obstetrics, Heze Municipal Hospital, Heze City, China
| | - Qiuxia Ren
- Department of Gynaecology and Obstetrics, Heze Municipal Hospital, Heze City, China
| | - Qingxiang Zeng
- Department of Gynaecology and Obstetrics, Heze Municipal Hospital, Heze City, China
| | - Xiaocui He
- Department of Gynaecology and Obstetrics, Heze Municipal Hospital, Heze City, China
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Farhadi P, Yarani R, Kiani S, Mansouri K. Perfluorocarbon as an adjuvant for tumor anti-angiogenic therapy: Relevance to hypoxia and HIF-1. Med Hypotheses 2020; 146:110357. [PMID: 33208240 DOI: 10.1016/j.mehy.2020.110357] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/15/2020] [Accepted: 10/23/2020] [Indexed: 12/17/2022]
Abstract
Lack of vascularization results in increased demand for oxygen and creates a defined feature of the tumor microenvironment known as tumor hypoxia. It is well established that in response to hypoxia, hypoxia-inducible factor-1 α (HIF-1α) is induced which is an important factor in angiogenesis, invasion and metastasis. In turn, HIF-1α regulates the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF). Ascribed to abnormal characteristics of tumor angiogenic networks, antiangiogenic therapy approaches can even worsen the hypoxic condition and can create cancer cells with stemness features. Hence oxygen delivery via perfluorocarbon (PFC) to hypoxic sites seems to result in unstable HIF expression and consequent inactivation of angiogenesis cascade and metastasis and therefore, inhibition of cancer cells stemness.
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Affiliation(s)
- Pegah Farhadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Sarah Kiani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Oncul S, Amero P, Rodriguez-Aguayo C, Calin GA, Sood AK, Lopez-Berestein G. Long non-coding RNAs in ovarian cancer: expression profile and functional spectrum. RNA Biol 2020; 17:1523-1534. [PMID: 31847695 PMCID: PMC7567512 DOI: 10.1080/15476286.2019.1702283] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 12/16/2022] Open
Abstract
Long non-coding RNAs (lncRNAs), initially recognized as byproducts of the transcription process, have been proven to play crucial modulatory roles in preserving overall homoeostasis of cells and tissues. Furthermore, aberrant levels of these transcripts have been shown to contribute many diseases, including cancer. Among these, many aspects of ovarian cancer biology have been found to be regulated by lncRNAs, including cancer initiation, progression and dissemination. In this review, we summarize recent studies to highlight the various roles of lncRNAs in ovary in normal and pathological conditions, immune system, diagnosis, prognosis, and therapy. We address lncRNAs that have been extensively studied in ovarian cancer and their contribution to cellular dynamics.
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Affiliation(s)
- Selin Oncul
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Biochemistry, Faculty of Pharmacy, The University of Hacettepe, Ankara, Turkey
| | - Paola Amero
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George A. Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Park JB, Seo J, Park JW, Chun YS. Neddylation blockade induces HIF-1α driven cancer cell migration via upregulation of ZEB1. Sci Rep 2020; 10:18210. [PMID: 33097763 PMCID: PMC7585416 DOI: 10.1038/s41598-020-75286-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Neddylation is a process by which NEDD8 is covalently conjugated to target proteins by sequential enzymatic reaction. Its role in cancer cell migration has only been recently acknowledged. Previously in cancer cell migration, the epithelial to mesenchymal transition (EMT) process has been well-known to play an important role in both invasion and metastasis by promoting mesenchymal phenotype in epithelial cells. However, the role of neddylation in the EMT process and its mechanistic details are yet to be elucidated. We recently reported that neddylation plays a crucial role in cancer cell migration through the PI3K-Akt pathway. Here, we report that inhibiting neddylation activates the hypoxia-inducible factor 1α (HIF-1α) through the PI3K-Akt pathway, which eventually regulates the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) in various cancer cell lines. As induction of HIF-1α is known to deteriorate the state of cancer and EMT process is one of the hallmarks of metastasis in cancer, our findings uncover the role of neddylation between HIF-1α and ZEB1.
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Affiliation(s)
- Jun Bum Park
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Korea
| | - Jieun Seo
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Korea
| | - Jong-Wan Park
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Korea
| | - Yang-Sook Chun
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Korea. .,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 110-799, Korea. .,Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
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