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1
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Fan TWM, Higashi RM, Lane AN. Metabolic Reprogramming in Human Cancer Patients and Patient-Derived Models. Cold Spring Harb Perspect Med 2025; 15:a041552. [PMID: 39009444 PMCID: PMC12047743 DOI: 10.1101/cshperspect.a041552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
Stable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the "benchmark" for cancer models to recapitulate. It is particularly difficult to model patients' tumor microenvironment (TME) with its complex cell-cell/cell-matrix interactions, which shapes metabolic reprogramming crucial to cancer development/drug resistance. Patient-derived organotypic tissue cultures (PD-OTCs) represent a unique model that retains an individual patient's TME. PD-OTCs of non-small-cell lung cancer better recapitulated the in vivo metabolic reprogramming of patient tumors than the patient-derived tumor xenograft (PDTX), while enabling interrogation of immunometabolic response to modulators and TME-dependent resistance development. Patient-derived organoids (PDOs) are also good models for reconstituting TME-dependent metabolic reprogramming and for evaluating therapeutic responses. Single-cell based 'omics on combinations of PD-OTC and PDO models will afford an unprecedented understanding on TME dependence of human cancer metabolic reprogramming, which should translate into the identification of novel metabolic targets for regulating TME interactions and drug resistance.
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Affiliation(s)
- Teresa W-M Fan
- Center for Environmental and Systems Biochemistry; Markey Cancer Center; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Richard M Higashi
- Center for Environmental and Systems Biochemistry; Markey Cancer Center; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Andrew N Lane
- Center for Environmental and Systems Biochemistry; Markey Cancer Center; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA
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2
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Seyfried TN, Lee DC, Duraj T, Ta NL, Mukherjee P, Kiebish M, Arismendi-Morillo G, Chinopoulos C. The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer. J Bioenerg Biomembr 2025:10.1007/s10863-025-10059-w. [PMID: 40199815 DOI: 10.1007/s10863-025-10059-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.
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Affiliation(s)
- Thomas N Seyfried
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA.
| | - Derek C Lee
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | - Tomas Duraj
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | - Nathan L Ta
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | - Purna Mukherjee
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | | | - Gabriel Arismendi-Morillo
- Facultad de Medicina, Instituto de Investigaciones Biológicas, Universidad del Zulia, Maracaibo, Venezuela
- Department of Medicine, Faculty of Health Sciences, University of Deusto, Bilbao (Bizkaia), Spain
| | - Christos Chinopoulos
- Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
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3
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Romero Rodríguez MI, Vargas Pino JC, Sierra-Ballén EL. Tumor Growth, Proliferation and Diffusion in Osteosarcoma. Acta Biotheor 2025; 73:4. [PMID: 40100437 PMCID: PMC11920320 DOI: 10.1007/s10441-025-09494-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 02/23/2025] [Indexed: 03/20/2025]
Abstract
Osteosarcoma is the most common primary bone cancer. According to medical and biological studies, it has a high genetic complexity, thus, to differentiate the mechanisms of appearance and evolution of this disease is a difficult task. In this paper, we use three simplest and well known mathematical models to describe the behavior of several cell lines of osteosarcoma. First, we use a potential law to describe the tumor growth in immunosuppressed mice; with it we show that the variation of tumor growth has a sublinear behavior without the blow-up phenomenon. Second, the logistic model is used to obtain a good aproximation to the rates of proliferation in cell confluency in in vitro experiments. Third, we use a linear reaction-diffusion model; with it, we describe the diffusion behavior for some cell lines. These three models allow us to give a classification of cell lines according to the rates of tumor growth and proliferation and to the diffusion coefficient. A relationship is found between the rates of the tumor growth, the diffusion coefficient and tumorigenicity. Experimental data are extracted from Lauvrak et al. (British Journal of Cancer 109(8):2228-2236, 2013).
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Affiliation(s)
- M I Romero Rodríguez
- Departamento de matemáticas. Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Km 7 Cajicá-Zipaquirá, Cajicá, Cundinamarca, 250240, Colombia.
| | - J C Vargas Pino
- Ingeniería Biomédica. Facultad de Ingeniería., Universidad Militar Nueva Granada, Km 7 Cajicá_Zipaquirá, Cajicá, Cundinamarca, 250240, Colombia
| | - E L Sierra-Ballén
- Ingeniería Multimedia. Facultad de Ingeniería, Universidad Militar Nueva Granada, Km 7 Cajicá-Zipaquirá, Cajicá, Cundinamarca, 250240, Colombia
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4
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Jonker PB, Sadullozoda M, Cognet G, Saab JJA, Sokol KH, Wu VX, Kumari D, Sheehan C, Ozgurses ME, Agovino D, Croley G, Patel SA, Bock-Hughes A, Macleod KF, Shah H, Coloff JL, Lien EC, Muir A. Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.10.642426. [PMID: 40161789 PMCID: PMC11952453 DOI: 10.1101/2025.03.10.642426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors perturb cellular metabolic activity, which imposes metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cell metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. As a consequence of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturatedenriched fat sources.
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Affiliation(s)
- Patrick B. Jonker
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Mumina Sadullozoda
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Guillaume Cognet
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Juan J. Apiz Saab
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Kelly H. Sokol
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, Michigan, USA, 49503
| | - Violet X. Wu
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Deepa Kumari
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Colin Sheehan
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Mete E. Ozgurses
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA, 60612
| | - Darby Agovino
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Grace Croley
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Smit A. Patel
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Althea Bock-Hughes
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Kay F. Macleod
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
| | - Hardik Shah
- Metabolomics Platform, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA, 60637
| | - Jonathan L. Coloff
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA, 60612
| | - Evan C. Lien
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, Michigan, USA, 49503
| | - Alexander Muir
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA, 60637
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5
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Ghimire K, Awasthi BP, Yadav K, Lee J, Kim H, Jeong BS, Kim JA. Prostate cancer-selective anticancer action of an oxindole derivative via HO-1-mediated disruption of metabolic reprogramming. Chem Biol Interact 2025; 408:111393. [PMID: 39842705 DOI: 10.1016/j.cbi.2025.111393] [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: 11/13/2024] [Revised: 12/26/2024] [Accepted: 01/20/2025] [Indexed: 01/24/2025]
Abstract
Prostate cancer, the second leading cause of cancer-related mortality in men, exhibits distinct metabolic reprogramming involving zinc and citrate metabolism. This study investigated whether targeting this unique metabolic profile could offer an effective therapeutic approach. A series of novel oxindole derivatives were synthesized and evaluated for their inhibitory effects on transcription factors (TFs) and antiproliferative activity across various cancer cell lines. Among these, compound 3D showed the strongest inhibition of master TFs (HIF-1α, c-Myc, and SP-1) and demonstrated selective antiproliferative activity in prostate cancer cells. In PC-3 and LNCaP cells, compound 3D suppressed aerobic glycolysis by downregulating lactate-modulating genes (LDHA, MCT1/4, and CAIX) and the zinc influx transporter (ZIP1), without affecting the zinc efflux transporter (ZnT4). Notably, 3D selectively increased heme oxygenase-1 (HO-1) levels in prostate cancer cells, as shown by the proteome profiler oncogene array assay and confirmed by Western blotting. This response was reversed by ZnCl2 treatment. The decreases in LDHA, mitochondrial mass (measured by FACS), and cell proliferation induced by compound 3D were blocked by HO-1-IN-1, an HO-1 inhibitor, and ZnCl2. Furthermore, 3D induced a more pronounced reduction in the oxygen consumption rate (OCR) than in the extracellular acidification rate (EACR), indicating a strong effect on oxidative metabolism. 3D exhibited dose-dependent antitumour efficacy in vivo comparable to that of docetaxel. These findings reveal that the oxindole derivative 3D substantially lowers intracellular zinc levels, yielding potent antitumour effects in prostate cancer through HO-1 upregulation, which impairs mitochondrial function more significantly than aerobic glycolysis.
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Affiliation(s)
- Kalpana Ghimire
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | | | - Kiran Yadav
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jiwoo Lee
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hyunjin Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Byeong-Seon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
| | - Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
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6
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Teuter M, Hu Y, Ross TL, Lolatte K, Ott M, Bengel FM, Balakrishnan A, Bankstahl JP. Longitudinal multi-tracer imaging of hepatocellular carcinoma identifies novel stage- and oncogene-specific changes. Nucl Med Biol 2025; 144-145:109000. [PMID: 39970776 DOI: 10.1016/j.nucmedbio.2025.109000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, globally. There is a need for novel biomarkers for early detection and novel, effective targeted therapies. Molecular imaging can faithfully visualize, characterize and quantify specific relevant biological processes. BASIC PROCEDURE We performed longitudinal dedicated small-animal positron emission tomography-computed tomography (PET/CT) imaging to analyze changes in glucose metabolism using [18F]fluorodeoxyglucose ([18F]FDG), amino acid turnover with [18F]fluoroethyltyrosine ([18F]FET), and chemokine receptor expression using [68Ga]pentixafor targeting CXCR4, during stages of early tumor development, overt HCC and regression. We used two conditional transgenic mouse models of HCC, driven by clinically relevant oncogenes c-MYC (LT2/MYC) or HRASV12 (LT2/RAS). Conditional doxycycline-regulated mouse models, enable liver-specific oncogene activation or inhibition, leading to liver tumor development and regression, respectively. Correlation of our PET/CT findings with our gene expression and metabolomics data and with histological analyses followed. MAIN FINDINGS We show PET/CT identifies HCC stage-specific and oncogene-specific molecular changes that may serve as potential novel biomarkers and therapeutic targets. Glucose metabolism and CXCR4 chemokine expression are differentially deregulated during HCC development in an oncogene-specific manner. Our [18F]FDG results correlated with glucose transporter GLUT1 gene expression and with our metabolomics data. Increased expression of CXCR4 and CD68 inflammatory markers mirrored [68Ga]pentixafor results in LT2/MYC mice. FET-based measurement of amino acid turnover are insensitive to stages of HCC-development, in our studies. Concurrently, no significant changes in expression of tyrosine metabolism genes were observed. PRINCIPAL CONCLUSIONS Our study highlights that identified changes in targeted molecular imaging can facilitate a better understanding of underlying biological processes and may help guide novel oncogene-specific targeted anti-tumor therapies in HCC, with promising translational potential.
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Affiliation(s)
- Mari Teuter
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Yuhai Hu
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany
| | - Tobias L Ross
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Kelsey Lolatte
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Michael Ott
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany
| | - Frank M Bengel
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany.
| | - Jens P Bankstahl
- Department of Nuclear Medicine, Hannover Medical School, Germany.
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7
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Rojas-Pirela M, Andrade-Alviárez D, Rojas V, Marcos M, Salete-Granado D, Chacón-Arnaude M, Pérez-Nieto MÁ, Kemmerling U, Concepción JL, Michels PAM, Quiñones W. Exploring glycolytic enzymes in disease: potential biomarkers and therapeutic targets in neurodegeneration, cancer and parasitic infections. Open Biol 2025; 15:240239. [PMID: 39904372 PMCID: PMC11793985 DOI: 10.1098/rsob.240239] [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: 08/26/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 02/06/2025] Open
Abstract
Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it is responsible for generating ATP in the cell through the conversion of glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed into the electron chain in the mitochondria to produce additional ATP by oxidative phosphorylation), as well as for producing intermediates that can serve as substrates for other metabolic processes. Glycolysis takes place through 10 consecutive chemical reactions, each of which is catalysed by a specific enzyme. Although energy transduction by glucose metabolism is the main function of this pathway, involvement in virulence, growth, pathogen-host interactions, immunomodulation and adaptation to environmental conditions are other functions attributed to this metabolic pathway. In humans, where glycolysis occurs mainly in the cytosol, the mislocalization of some glycolytic enzymes in various other subcellular locations, as well as alterations in their expression and regulation, has been associated with the development and progression of various diseases. In this review, we describe the role of glycolytic enzymes in the pathogenesis of diseases of clinical interest. In addition, the potential role of these enzymes as targets for drug development and their potential for use as diagnostic and prognostic markers of some pathologies are also discussed.
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Affiliation(s)
- Maura Rojas-Pirela
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca37007, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
- Servicio de Medicina Interna, Hospital Universitario de Salamanca, Salamanca37007, Spain
| | - Diego Andrade-Alviárez
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| | - Verónica Rojas
- Instituto de Biología, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso2373223, Chile
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca37007, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
- Servicio de Medicina Interna, Hospital Universitario de Salamanca, Salamanca37007, Spain
| | - Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca37007, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
| | - Marirene Chacón-Arnaude
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| | - María Á. Pérez-Nieto
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
- Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León, Soria42002, Spain
| | - Ulrike Kemmerling
- Instituto de Ciencias Biomédicas, Universidad de Chile, Facultad de Medicina, Santiago de Chile8380453, Chile
| | - Juan Luis Concepción
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| | - Paul A. M. Michels
- School of Biological Sciences, University of Edinburgh, The King’s Buildings, EdinburghEH9 3FL, UK
| | - Wilfredo Quiñones
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
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8
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Daimiel Naranjo I, Bhowmik A, Basukala D, Lo Gullo R, Mazaheri Y, Kapetas P, Eskreis-Winkler S, Pinker K, Thakur SB. Assessment of Hypoxia in Breast Cancer: Emerging Functional MR Imaging and Spectroscopy Techniques and Clinical Applications. J Magn Reson Imaging 2025; 61:83-96. [PMID: 38703143 DOI: 10.1002/jmri.29424] [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: 02/29/2024] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/06/2024] Open
Abstract
Breast cancer is one of the most prevalent forms of cancer affecting women worldwide. Hypoxia, a condition characterized by insufficient oxygen supply in tumor tissues, is closely associated with tumor aggressiveness, resistance to therapy, and poor clinical outcomes. Accurate assessment of tumor hypoxia can guide treatment decisions, predict therapy response, and contribute to the development of targeted therapeutic interventions. Over the years, functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques have emerged as promising noninvasive imaging options for evaluating hypoxia in cancer. Such techniques include blood oxygen level-dependent (BOLD) MRI, oxygen-enhanced MRI (OE) MRI, chemical exchange saturation transfer (CEST) MRI, and proton MRS (1H-MRS). These may help overcome the limitations of the routinely used dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) techniques, contributing to better diagnosis and understanding of the biological features of breast cancer. This review aims to provide a comprehensive overview of the emerging functional MRI and MRS techniques for assessing hypoxia in breast cancer, along with their evolving clinical applications. The integration of these techniques in clinical practice holds promising implications for breast cancer management. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.
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Affiliation(s)
- Isaac Daimiel Naranjo
- Department of Radiology, HM Hospitales, Madrid, Spain
- School of Medicine, Universidad CEU San Pablo, Madrid, Spain
| | - Arka Bhowmik
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dibash Basukala
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Radiology, Center for Advanced Imaging Innovation and Research (CAI2R), Center for Biomedical Imaging, NYU Langone Health, New York, New York, USA
| | - Roberto Lo Gullo
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Yousef Mazaheri
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Panagiotis Kapetas
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Sarah Eskreis-Winkler
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Katja Pinker
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Sunitha B Thakur
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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9
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Anandi L, Garcia J, Ros M, Janská L, Liu J, Carmona-Fontaine C. Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment. Life Sci Alliance 2025; 8:e202403053. [PMID: 39419548 PMCID: PMC11487089 DOI: 10.26508/lsa.202403053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
Ischemic conditions such as hypoxia and nutrient starvation, together with interactions with stromal cells, are critical drivers of metastasis. These conditions arise deep within tumor tissues, and thus, observing nascent metastases is exceedingly challenging. We thus developed the 3MIC-an ex vivo model of the tumor microenvironment-to study the emergence of metastatic features in tumor cells in a 3-dimensional (3D) context. Here, tumor cells spontaneously create ischemic-like conditions, allowing us to study how tumor spheroids migrate, invade, and interact with stromal cells under different metabolic conditions. Consistent with previous data, we show that ischemia increases cell migration and invasion, but the 3MIC allowed us to directly observe and perturb cells while they acquire these pro-metastatic features. Interestingly, our results indicate that medium acidification is one of the strongest pro-metastatic cues and also illustrate using the 3MIC to test anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC can help dissecting the complexity of the tumor microenvironment for the direct observation and perturbation of tumor cells during the early metastatic process.
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Affiliation(s)
- Libi Anandi
- Center for Genomics & Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Jeremy Garcia
- Center for Genomics & Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Manon Ros
- Center for Genomics & Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Libuše Janská
- Center for Genomics & Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Josephine Liu
- Center for Genomics & Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Carlos Carmona-Fontaine
- Center for Genomics & Systems Biology, Department of Biology, New York University, New York, NY, USA
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10
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Li X, Zhang L, Liu C, He Y, Li X, Xu Y, Gu C, Wang X, Wang S, Zhang J, Liu J. Construction of mitochondrial quality regulation genes-related prognostic model based on bulk-RNA-seq analysis in multiple myeloma. Biofactors 2025; 51:e2135. [PMID: 39446019 DOI: 10.1002/biof.2135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/05/2024] [Indexed: 10/25/2024]
Abstract
Mitochondrial quality regulation plays an important role in affecting the treatment sensitivity of multiple myeloma (MM). We aimed to develop a mitochondrial quality regulation genes (MQRGs)-related prognostic model for MM patients. The Genomic Data Commons-MM of bulk RNA-seq, mutation, and single-cell RNA-seq (scRNA-seq) dataset were downloaded, and the MQRGs gene set was collected previous study. "maftools" and CIBERSORT were used for mutation and immune-infiltration analysis. Subsequently, the "ConsensusClusterPlus" was used to perform the unsupervised clustering analysis, "survminer" and "ssGSEA" R package was used for the Kaplan-Meier survival and enrichment analysis, "limma" R, univariate and Least Absolute Shrinkage and Selection Operator Cox were used for RiskScore model. The "timeROC" R package was used for Receiver Operating Characteristic Curve analysis. Finally, the "Seurat" R package was used for scRNA-seq analysis. These MQRGs are mainly located on chromosome-1,2,3,7, and 22 and had significant expression differences among age, gender, and stage groups, in which PPARGC1A and PPARG are the high mutation genes. Most MQRGs expression are closely associated with the plasma cells infiltration and can divide the patients into 2 different prognostic clusters (C1, C2). Then, 8 risk models were screened from 60 DEGs for RiskScore, which is an independent prognostic factor and effectively divided the patients into high and low risk groups with significant difference of immune checkpoint expression. Nomogram containing RiskScore can accurately predict patient prognosis, and a series of specific transcription factor PRDM1 and IRF1 were identified. We described the based molecular features and developed a high effective MQRGs-related prognostic model in MM.
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Affiliation(s)
- Xiaohui Li
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ling Zhang
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chengcheng Liu
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yi He
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xudong Li
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yichuan Xu
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Cuiyin Gu
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiaozhen Wang
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shuoting Wang
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jingwen Zhang
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiajun Liu
- Hematology Department, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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11
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Kumari S, Gupta S, Jamil A, Tabatabaei D, Karakashev S. Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy. J Cell Physiol 2025; 240:e31495. [PMID: 39676338 DOI: 10.1002/jcp.31495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024]
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.
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Affiliation(s)
- Sangeeta Kumari
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Shraddha Gupta
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Aisha Jamil
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Deyana Tabatabaei
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
| | - Sergey Karakashev
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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12
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Yuan S, Ou W, Mi X, Hou J. Enhancing lobaplatin sensitivity in lung adenocarcinoma through inhibiting LDHA-targeted metabolic pathways. PLoS One 2024; 19:e0310825. [PMID: 39680520 DOI: 10.1371/journal.pone.0310825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 09/03/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), is associated with high incidence and mortality rates. Effective treatment options are limited due to the frequent development of multidrug resistance, making it crucial to identify new therapeutic targets and sensitizing agents. This study investigates the role of Lactate dehydrogenase A (LDHA) in enhancing the chemotherapy sensitivity of Lobaplatin (LBP) in LUAD. METHODS Bioinformatics analyses were performed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to assess LDHA expression in LUAD tissues. LUAD cell lines A549 and NCL-H1975 were treated with siRNA targeting LDHA and the small molecule inhibitor Oxamate. We measured changes in lactate production, ATP levels, NAD+ and pyruvate levels, and assessed cell viability. The chemotherapy sensitivity to Lobaplatin was evaluated, and key signaling pathways related to chemotherapy resistance were analyzed. RESULTS The inhibition of LDHA resulted in a significant reduction in lactate production and ATP levels, along with an increase in NAD+ and pyruvate levels. These metabolic alterations led to decreased cell viability and enhanced sensitivity to Lobaplatin. The study identified the PI3K/AKT signaling pathway as a critical mediator of this enhanced sensitivity, with reduced phosphorylation of AKT observed upon LDHA inhibition. Furthermore, the combination of LDHA inhibition and Lobaplatin treatment demonstrated a synergistic effect, significantly inhibiting tumor growth and highlighting the potential of LDHA as a therapeutic target to overcome drug resistance in LUAD. CONCLUSION Targeting LDHA and disrupting lactate metabolism and its signaling pathways can effectively enhance the sensitivity of LUAD to Lobaplatin, providing a promising approach to overcoming multidrug resistance. These findings offer valuable insights into developing new treatment strategies for lung adenocarcinoma, emphasizing the role of metabolic pathways in cancer therapy.
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Affiliation(s)
- Siyu Yuan
- Department of Clinical Nutrition, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wenjie Ou
- School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Xuguang Mi
- Department of central laboratory, Jilin Provincial People's Hospital, Changchun, Jilin, China
| | - Junjie Hou
- Department of Comprehensive Oncology, Jilin Provincial People's Hospital, Changchun, Jilin, China
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13
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Jonker PB, Muir A. Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment. Dis Model Mech 2024; 17:dmm050814. [PMID: 39284708 PMCID: PMC11423921 DOI: 10.1242/dmm.050814] [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] [Indexed: 09/27/2024] Open
Abstract
Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.
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Affiliation(s)
- Patrick B Jonker
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA
| | - Alexander Muir
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA
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14
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Malla A, Gupta S, Sur R. Glycolytic enzymes in non-glycolytic web: functional analysis of the key players. Cell Biochem Biophys 2024; 82:351-378. [PMID: 38196050 DOI: 10.1007/s12013-023-01213-5] [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: 10/30/2023] [Accepted: 12/26/2023] [Indexed: 01/11/2024]
Abstract
To survive in the tumour microenvironment, cancer cells undergo rapid metabolic reprograming and adaptability. One of the key characteristics of cancer is increased glycolytic selectivity and decreased oxidative phosphorylation (OXPHOS). Apart from ATP synthesis, glycolysis is also responsible for NADH regeneration and macromolecular biosynthesis, such as amino acid biosynthesis and nucleotide biosynthesis. This allows cancer cells to survive and proliferate even in low-nutrient and oxygen conditions, making glycolytic enzymes a promising target for various anti-cancer agents. Oncogenic activation is also caused by the uncontrolled production and activity of glycolytic enzymes. Nevertheless, in addition to conventional glycolytic processes, some glycolytic enzymes are involved in non-canonical functions such as transcriptional regulation, autophagy, epigenetic changes, inflammation, various signaling cascades, redox regulation, oxidative stress, obesity and fatty acid metabolism, diabetes and neurodegenerative disorders, and hypoxia. The mechanisms underlying the non-canonical glycolytic enzyme activities are still not comprehensive. This review summarizes the current findings on the mechanisms fundamental to the non-glycolytic actions of glycolytic enzymes and their intermediates in maintaining the tumor microenvironment.
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Affiliation(s)
- Avirup Malla
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, Kolkata, India
| | - Suvroma Gupta
- Department of Aquaculture Management, Khejuri college, West Bengal, Baratala, India.
| | - Runa Sur
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, Kolkata, India.
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15
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Zorova LD, Abramicheva PA, Andrianova NV, Babenko VA, Zorov SD, Pevzner IB, Popkov VA, Semenovich DS, Yakupova EI, Silachev DN, Plotnikov EY, Sukhikh GT, Zorov DB. Targeting Mitochondria for Cancer Treatment. Pharmaceutics 2024; 16:444. [PMID: 38675106 PMCID: PMC11054825 DOI: 10.3390/pharmaceutics16040444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 03/20/2024] [Indexed: 04/28/2024] Open
Abstract
There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy.
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Affiliation(s)
- Ljubava D. Zorova
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Polina A. Abramicheva
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
| | - Nadezda V. Andrianova
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
| | - Valentina A. Babenko
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Savva D. Zorov
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Irina B. Pevzner
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Vasily A. Popkov
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Dmitry S. Semenovich
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
| | - Elmira I. Yakupova
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
| | - Denis N. Silachev
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
| | - Egor Y. Plotnikov
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Gennady T. Sukhikh
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Dmitry B. Zorov
- A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (L.D.Z.); (P.A.A.); (V.A.B.); (S.D.Z.); (I.B.P.); (V.A.P.); (D.S.S.); (E.I.Y.); (D.N.S.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
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16
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Barba I, Carrillo-Bosch L, Seoane J. Targeting the Warburg Effect in Cancer: Where Do We Stand? Int J Mol Sci 2024; 25:3142. [PMID: 38542116 PMCID: PMC10970388 DOI: 10.3390/ijms25063142] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/06/2025] Open
Abstract
The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.
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Affiliation(s)
- Ignasi Barba
- Faculty of Medicine, University of Vic-Central University of Catalonia, 08500 Vic, Catalonia, Spain
- Vall d’Hebron Institute of Oncology (VHIO), CIBERONC, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Laura Carrillo-Bosch
- Vall d’Hebron Institute of Oncology (VHIO), CIBERONC, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Joan Seoane
- Vall d’Hebron Institute of Oncology (VHIO), CIBERONC, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
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17
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Fei X, Du X, Wang J, Liu J, Gong Y, Zhao Z, Cao Z, Fu Q, Zhu Y, Dong L, Dong B, Pan J, Sun W, Xie S, Xue W. Precise diagnosis and risk stratification of prostate cancer by comprehensive serum metabolic fingerprints: a prediction model study. Int J Surg 2024; 110:1450-1462. [PMID: 38181121 PMCID: PMC10942223 DOI: 10.1097/js9.0000000000001033] [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: 08/03/2023] [Accepted: 12/11/2023] [Indexed: 01/07/2024]
Abstract
OBJECTIVES Prostate cancer (PCa) is one of the most common malignancies in men worldwide and has caused increasing clinical morbidity and mortality, making timely diagnosis and accurate staging crucial. The authors introduced a novel approach based on mass spectrometry for precise diagnosis and stratification of PCa to facilitate clinical decision-making. METHODS Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis of trace blood samples was combined with machine learning algorithms to construct diagnostic and stratification models. A total of 367 subjects, comprising 181 with PCa and 186 with non-PCa were enrolled. Additional 60 subjects, comprising 30 with PCa and 30 with non-PCa were enrolled as an external cohort for validation. Subsequent metabolomic analysis was carried out using Autoflex MALDI-TOF, and the mass spectra were introduced into various algorithms to construct different models. RESULTS Serum metabolic fingerprints were successfully obtained from 181 patients with PCa and 186 patients with non-PCa. The diagnostic model based on the eight signals demonstrated a remarkable area under curve of 100% and was validated in the external cohort with the area under curve of 87.3%. Fifteen signals were selected for enrichment analysis, revealing the potential metabolic pathways that facilitate tumorigenesis. Furthermore, the stage prediction model with an overall accuracy of 85.9% precisely classified subjects with localized disease and those with metastasis. The risk stratification model, with an overall accuracy of 89.6%, precisely classified the subjects as low-risk and high-risk. CONCLUSIONS Our study facilitated the timely diagnosis and risk stratification of PCa and provided new insights into the underlying mechanisms of metabolic alterations in PCa.
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Affiliation(s)
| | | | | | | | | | - Zejun Zhao
- Department of Ultrasound, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Zhibin Cao
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong, People’s Republic of China
| | - Qibo Fu
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong, People’s Republic of China
| | | | | | | | | | - Wenshe Sun
- Department of Urology, Jiading District Central Hospital, Shanghai University of Medicine and Health Sciences, Shanghai
| | - Shaowei Xie
- Department of Ultrasound, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine
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Liao M, Yao D, Wu L, Luo C, Wang Z, Zhang J, Liu B. Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer. Acta Pharm Sin B 2024; 14:953-1008. [PMID: 38487001 PMCID: PMC10935242 DOI: 10.1016/j.apsb.2023.12.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 03/17/2024] Open
Abstract
Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells. Key enzymes involved in this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, and PKM2. Moreover, the expression of transcriptional regulatory factors and proteins, such as FOXM1, p53, NF-κB, HIF1α, and c-Myc, can also influence cancer progression. Furthermore, lncRNAs, miRNAs, and circular RNAs play a vital role in directly regulating the Warburg effect. Additionally, gene mutations, tumor microenvironment remodeling, and immune system interactions are closely associated with the Warburg effect. Notably, the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment. This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.
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Affiliation(s)
- Minru Liao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dahong Yao
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China
| | - Lifeng Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chaodan Luo
- Department of Psychology, University of Southern California, Los Angeles, CA 90089, USA
| | - Zhiwen Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Jin Zhang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Bo Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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19
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Michelucci A, Sforna L, Franciolini F, Catacuzzeno L. Hypoxia, Ion Channels and Glioblastoma Malignancy. Biomolecules 2023; 13:1742. [PMID: 38136613 PMCID: PMC10742235 DOI: 10.3390/biom13121742] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen levels have been shown to control several critical aspects of tumor aggressiveness, such as migration/invasion and cell death resistance, but the underlying mechanisms are still unclear. GBM cells express abundant K+ and Cl- channels, whose activity supports cell volume and membrane potential changes, critical for cell proliferation, migration and death. Volume-regulated anion channels (VRAC), which mediate the swelling-activated Cl- current, and the large-conductance Ca2+-activated K+ channels (BK) are both functionally upregulated in GBM cells, where they control different aspects underlying GBM malignancy/aggressiveness. The functional expression/activity of both VRAC and BK channels are under the control of the oxygen levels, and these regulations are involved in the hypoxia-induced GBM cell aggressiveness. The present review will provide a comprehensive overview of the literature supporting the role of these two channels in the hypoxia-mediated GBM malignancy, suggesting them as potential therapeutic targets in the treatment of GBM.
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Affiliation(s)
- Antonio Michelucci
- Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy; (L.S.); (F.F.)
| | | | | | - Luigi Catacuzzeno
- Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy; (L.S.); (F.F.)
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20
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Zhang Y, Xing A, He J, Wang F, Li Z, Sun B. Curettage combined with bone cavity opening reduces recurrence of the mandibular conventional ameloblastoma and effectively preserves the mandible: a retrospective study. BMC Oral Health 2023; 23:885. [PMID: 37986074 PMCID: PMC10658885 DOI: 10.1186/s12903-023-03660-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 11/12/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Patients with mandibular conventional ameloblastoma undergoing radical surgical treatment experience greater trauma and often find it challenging to accept, whereas conservative therapy is associated with a higher recurrence rate. In this study, we have improved traditional conservative treatment for mandibular conventional ameloblastoma by curettage combined with bone cavity opening (Cur/BCO). This retrospective study aimed to evaluate the effectiveness of the Cur/BCO treatment by comparing its recurrence rate and bone mineral density (BMD) growth rate with the traditional conservative treatment approach. METHODS A total of 40 patients, meeting the study's inclusion and exclusion criteria from 2012 to 2020, were screened, with 20 in the modified group and 20 in the traditional group. ImageJ (RRID: SCR_003070) software was employed for measuring image indices. All data were analyzed using T-test, Chi-square test and Fisher exact test in SPSS 26.0 (p = 0.05). RESULTS The incidence of recurrence was significantly lower in the modified group, at only 5%, compared to 35% in the traditional group (p < 0.05). Regarding bone mineral density (BMD) growth rate, the average value in the modified group was 0.0862 ± 0.2302 (/month), significantly higher than the average value of 0.0608 ± 0.2474 (/month) in the traditional group (p < 0.05). CONCLUSIONS In this study, it was found that the recurrence rate of the modified conservative treatment (Cur/BCO) was lower than that of the traditional conservative treatment for managing mandibular conventional ameloblastoma. Furthermore, the BMD growth rate was quicker in the modified group. Thus, Cur/BCO could be considered as a viable option for the conservative treatment of mandibular conventional ameloblastoma.
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Affiliation(s)
- Yuan Zhang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Qinghua Road 1500, Changchun, Jilin Province, 130021, P. R. China
| | - Aili Xing
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Qinghua Road 1500, Changchun, Jilin Province, 130021, P. R. China
| | - Jingya He
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Qinghua Road 1500, Changchun, Jilin Province, 130021, P. R. China
| | - Feng Wang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Qinghua Road 1500, Changchun, Jilin Province, 130021, P. R. China
| | - Zhongrui Li
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Qinghua Road 1500, Changchun, Jilin Province, 130021, P. R. China
| | - Bin Sun
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Qinghua Road 1500, Changchun, Jilin Province, 130021, P. R. China.
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21
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Grigoriadis G, Koufakis T, Kotsa K. Epidemiological, Pathophysiological, and Clinical Considerations on the Interplay between Thyroid Disorders and Type 2 Diabetes Mellitus. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2013. [PMID: 38004062 PMCID: PMC10673571 DOI: 10.3390/medicina59112013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/12/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023]
Abstract
Thyroid disorders (TD) and diabetes mellitus (DM) are the two endocrinopathies with the highest prevalence in the general population that frequently coexist. Thyroid dysfunction is more common in people with type 2 diabetes mellitus (T2DM) compared to normoglycemic individuals. Untreated TD can impair glycemic control, increasing the risk of diabetes complications. Hyperinsulinemia can affect the morphology of the thyroid gland by promoting the proliferation of thyroid tissue and increasing the size of thyroid nodules. Metformin can confer benefits in both endocrinopathies, while other antidiabetics, such as sulfonylureas, can negatively affect thyroid function. Animal and human observational data suggest an increased risk of medullary thyroid carcinoma after treatment with glucagon-like peptide-1 receptor agonists. However, randomized trials have so far been reassuring. Furthermore, some observational studies suggest an association between thyroid cancer and T2DM, especially in women. This narrative review aims to shed light on the epidemiological, pathophysiological, and clinical aspects of the interplay between TD and T2DM. Taking into account the important clinical implications of the coexistence of T2DM and TD, proper screening and management strategies are needed for both endocrinopathies to ensure optimal patient care.
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Affiliation(s)
- Gregory Grigoriadis
- Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece;
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22
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Zefferino R, Conese M. A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects. Vaccines (Basel) 2023; 11:1701. [PMID: 38006033 PMCID: PMC10674257 DOI: 10.3390/vaccines11111701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/07/2023] [Accepted: 10/19/2023] [Indexed: 11/26/2023] Open
Abstract
Is it possible to have an available vaccine that eradicates cancer? Starting from this question, this article tries to verify the state of the art, proposing a different approach to the issue. The variety of cancers and different and often unknown causes of cancer impede, except in some cited cases, the creation of a classical vaccine directed at the causative agent. The efforts of the scientific community are oriented toward stimulating the immune systems of patients, thereby preventing immune evasion, and heightening chemotherapeutic agents effects against cancer. However, the results are not decisive, because without any warning signs, metastasis often occurs. The purpose of this paper is to elaborate on a vaccine that must be administered to a patient in order to prevent metastasis; metastasis is an event that leads to death, and thus, preventing it could transform cancer into a chronic disease. We underline the fact that the field has not been studied in depth, and that the complexity of metastatic processes should not be underestimated. Then, with the aim of identifying the target of a cancer vaccine, we draw attention to the presence of the paradoxical actions of different mechanisms, pathways, molecules, and immune and non-immune cells characteristic of the tumor microenvironment at the primary site and pre-metastatic niche in order to exclude possible vaccine candidates that have opposite effects/behaviors; after a meticulous evaluation, we propose possible targets to develop a metastasis-targeting vaccine. We conclude that a change in the current concept of a cancer vaccine is needed, and the efforts of the scientific community should be redirected toward a metastasis-targeting vaccine, with the increasing hope of eradicating cancer.
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Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Massimo Conese
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
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23
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Paul SK, Dutta Chowdhury K, Dey SR, Paul A, Haldar R. Exploring the possibility of drug repurposing for cancer therapy targeting human lactate dehydrogenase A: a computational approach. J Biomol Struct Dyn 2023; 41:9967-9976. [PMID: 36576127 DOI: 10.1080/07391102.2022.2158134] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 11/12/2022] [Indexed: 12/29/2022]
Abstract
Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of cancer cells is found to be elevated and the dependence of cancer cells on anaerobic glycolysis is viewed as the reason for this elevation. Moreover, inhibition of LDHA activity has been shown to be effective in impairing the growth of tumors, making the LDHA as a potential target for cancer therapy. In this computational study, we have performed a pharmacophore based screening of approved drugs followed by a molecular docking based screening to find a few potential LDHA inhibitors. Molecular dynamics simulations have also been performed to examine the stability of the LDHA-drug complexes as obtained from the docking study. The result of the study showed that darunavir, moxalactam and eprosartan can bind to the active site of LDHA with high affinity in comparison to two known synthetic inhibitors of LDHA. The results of the molecular dynamics simulation showed that these drugs can bind stably with the enzyme through hydrogen bond and hydrophobic interactions. Hence, it is concluded that darunavir, moxalactam and eprosartan may be considered as potential inhibitors of LDHA and can be used for cancer therapy after proper validation of their effectiveness through in vitro, in vivo and clinical trials.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sanjay Kumar Paul
- Department of Zoology, Rammohan College, Kolkata, West Bengal, India
| | | | - Santi Ranjan Dey
- Department of Zoology, Rammohan College, Kolkata, West Bengal, India
| | - Ayantika Paul
- Department of Physiology, University of Calcutta, Kolkata, West Bengal, India
| | - Rajen Haldar
- Department of Physiology, University of Calcutta, Kolkata, West Bengal, India
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Kobayashi H, Yoshimoto C, Matsubara S, Shigetomi H, Imanaka S. A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:547-566. [PMID: 37842240 PMCID: PMC10571061 DOI: 10.20517/cdr.2023.49] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/03/2023] [Accepted: 08/07/2023] [Indexed: 10/17/2023]
Abstract
Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara 634-0813, Japan
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara 634-8522, Japan
| | - Chiharu Yoshimoto
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara 634-8522, Japan
- Department of Obstetrics and Gynecology, Nara Prefecture General Medical Center, Nara 630-8581, Japan
| | - Sho Matsubara
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara 634-8522, Japan
- Department of Medicine, Kei Oushin Clinic, Nishinomiya 663-8184, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara 634-8522, Japan
- Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, Nara 634-0001, Japan
| | - Shogo Imanaka
- Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara 634-0813, Japan
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara 634-8522, Japan
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Dang CV. Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus. Cold Spring Harb Perspect Med 2023; 13:a041530. [PMID: 37553212 PMCID: PMC10691493 DOI: 10.1101/cshperspect.a041530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
A century ago, Otto Warburg's work sparked the field of cancer metabolism, which has since taken a tortuous path. As evidence accumulated over the decades, consensus views of causes of cancer emerged, whereby genetic and epigenetic oncogenic drivers promoted immune evasion and induced new blood vessels and neoplastic metabolism to support tumor growth. Neoplastic cells abandon social cues of intercellular cooperation, escape tissue confinement, metastasize, and ultimately kill the host. Herein, key milestones in the study of cancer metabolism are chronicled with an emphasis on carbohydrate metabolism. The field began with a cancer cell-autonomous view that has been refined by a richer understanding of solid cancers as growing, immune-suppressive, complex organs comprising different cell types that are nourished by a variety of nutrients and variable amounts of oxygen through abnormal neovasculatures. Based on foundational historical studies, our current understanding of cancer metabolism offers a hopeful outlook for targeting metabolism to enhance cancer therapy.
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Affiliation(s)
- Chi V Dang
- Ludwig Institute for Cancer Research, New York, New York 10017, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21287, USA
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26
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Tardito S, MacKay C. Rethinking our approach to cancer metabolism to deliver patient benefit. Br J Cancer 2023; 129:406-415. [PMID: 37340094 PMCID: PMC10403540 DOI: 10.1038/s41416-023-02324-9] [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: 02/28/2023] [Revised: 05/25/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
Altered cellular metabolism is a major mechanism by which tumours support nutrient consumption associated with increased cellular proliferation. Selective dependency on specific metabolic pathways provides a therapeutic vulnerability that can be targeted in cancer therapy. Anti-metabolites have been used clinically since the 1940s and several agents targeting nucleotide metabolism are now well established as standard of care treatment in a range of indications. However, despite great progress in our understanding of the metabolic requirements of cancer and non-cancer cells within the tumour microenvironment, there has been limited clinical success for novel agents targeting pathways outside of nucleotide metabolism. We believe that there is significant therapeutic potential in targeting metabolic processes within cancer that is yet to be fully realised. However, current approaches to identify novel targets, test novel therapies and select patient populations most likely to benefit are sub-optimal. We highlight recent advances in technologies and understanding that will support the identification and validation of novel targets, re-evaluation of existing targets and design of optimal clinical positioning strategies to deliver patient benefit.
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Affiliation(s)
- Saverio Tardito
- The Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Craig MacKay
- Cancer Research Horizons, The Cancer Research UK Beatson Institute, Glasgow, UK.
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27
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Kamioka H, Yogosawa S, Oikawa T, Aizawa D, Ueda K, Saeki C, Haruki K, Shimoda M, Ikegami T, Nishikawa Y, Saruta M, Yoshida K. Dyrk2 gene transfer suppresses hepatocarcinogenesis by promoting the degradation of Myc and Hras. JHEP Rep 2023; 5:100759. [PMID: 37333975 PMCID: PMC10275997 DOI: 10.1016/j.jhepr.2023.100759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 03/06/2023] [Accepted: 03/21/2023] [Indexed: 06/20/2023] Open
Abstract
Background & Aims Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and has a poor prognosis. However, the molecular mechanisms underlying hepatocarcinogenesis and progression remain unknown. In vitro gain- and loss-of-function analyses in cell lines and xenografts revealed that dual-specificity tyrosine-regulated kinase 2 (DYRK2) influences tumour growth in HCC. Methods To investigate the role of Dyrk2 during hepatocarcinogenesis, we developed liver-specific Dyrk2 conditional knockout mice and an in vivo gene delivery system with a hydrodynamic tail vein injection and the Sleeping Beauty transposon. The antitumour effects of Dyrk2 gene transfer were investigated in a murine autologous carcinogenesis model. Results Dyrk2 expression was reduced in tumours, and that its downregulation was induced before hepatocarcinogenesis. Dyrk2 gene transfer significantly suppressed carcinogenesis. It also suppresses Myc-induced de-differentiation and metabolic reprogramming, which favours proliferative, and malignant potential by altering gene profiles. Dyrk2 overexpression caused Myc and Hras degradation at the protein level rather than at the mRNA level, and this degradation mechanism was regulated by the proteasome. Immunohistochemical analyses revealed a negative correlation between DYRK2 expression and MYC and longer survival in patients with HCC with high-DYRK2 and low-MYC expressions. Conclusions Dyrk2 protects the liver from carcinogenesis by promoting Myc and Hras degradation. Our findings would pave the way for a novel therapeutic approach using DYRK2 gene transfer. Impact and Implications Hepatocellular carcinoma (HCC) is one of the most common cancers, with a poor prognosis. Hence, identifying molecules that can become promising targets for therapies is essential to improve mortality. No studies have clarified the association between DYRK2 and carcinogenesis, although DYRK2 is involved in tumour growth in various cancer cells. This is the first study to show that Dyrk2 expression decreases during hepatocarcinogenesis and that Dyrk2 gene transfer is an attractive approach with tumour suppressive activity against HCC by suppressing Myc-mediated de-differentiation and metabolic reprogramming that favours proliferative and malignant potential via Myc and Hras degradation.
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Affiliation(s)
- Hiroshi Kamioka
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Satomi Yogosawa
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Daisuke Aizawa
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Masayuki Shimoda
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuji Nishikawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
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Anastasi E, Farina A, Granato T, Colaiacovo F, Pucci B, Tartaglione S, Angeloni A. Recent Insight about HE4 Role in Ovarian Cancer Oncogenesis. Int J Mol Sci 2023; 24:10479. [PMID: 37445657 DOI: 10.3390/ijms241310479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Currently, ovarian cancer (OC) is a target of intense biomarkers research because of its frequent late diagnosis and poor prognosis. Serum determination of Human epididymis protein 4 (HE4) is a very important early detection test. Most interestingly, HE4 plays a unique role in OC as it has been implicated not only in OC diagnosis but also in the prognosis and recurrence of this lethal neoplasm, actually acting as a clinical biomarker. There are several evidence about the predictive power of HE4 clinically, conversely less has been described concerning its role in OC oncogenesis. Based on these considerations, the main goal of this review is to clarify the role of HE4 in OC proliferation, angiogenesis, metastatization, immune response and also in the development of targeted therapy. Through a deeper understanding of its functions as a key molecule in the oncogenetic processes underlying OC, HE4 could be possibly considered as an essential resource not only for diagnosis but also for prognosis and therapy choice.
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Affiliation(s)
- Emanuela Anastasi
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Antonella Farina
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Teresa Granato
- CNR-IBPM, Institute of Molecular Biology and Pathology, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Flavia Colaiacovo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Beatrice Pucci
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Sara Tartaglione
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Antonio Angeloni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
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Yang M, Wang X, Ye Z, Liu T, Meng Y, Duan Y, Yuan X, Yue X, Deng W, Liu RY. Mitochondrial creatine kinase 1 regulates the cell cycle in non-small cell lung cancer via activation of cyclin-dependent kinase 4. Respir Res 2023; 24:111. [PMID: 37061730 PMCID: PMC10105958 DOI: 10.1186/s12931-023-02417-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 04/06/2023] [Indexed: 04/17/2023] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the main type of the most common malignant tumor in the world. Previous studies have shown that the expression level of mitochondrial creatine kinase 1 (CKMT1) is abnormal in NSCLC, but the mechanism of its effect remains unclear. Therefore, in this study, we intend to clarify the potential mechanism of CKMT1 in NSCLC and provide the theoretical basis for the clinical application of CKMT1. METHODS The function of CKMT1 in NSCLC was identified by analyzing the GEO dataset and evaluating using in vitro and in vivo models. Protein mass spectrometry was used to find proteins interacting with CKMT1, and Co-immunoprecipitation (Co-IP) and GST-pull down experiments were used to verify the interaction between proteins. The immunofluorescence (IF) assay was used to explore the functional position of CKMT1 in cells. The effect of CKMT1 expression level on the efficacy of paclitaxel (TAX) in the treatment of NSCLC was analyzed by a combined TAX experiment in vivo and in vitro. RESULTS CKMT1 expression was increased in NSCLC and CKMT1 promoted the proliferation of NSCLC cells in vitro and in vivo. CKMT1 knockdown resulted in a significantly increased G0/G1 fraction and decreased S phase cell fraction, indicating G1 phase arrest. Mechanically, the cyclin-dependent kinase 4 (CDK4) was identified to interact with CKMT1, and the crucial binding areas were focused on the DH domain of CKMT1 and the N- and C-terminal of CDK4. A fraction of the CDK4 proteins colocalize and interact with the CKMT1 at mitochondria, the level of phosphorylated CDK4 was regulated by CKMT1. Hence, the decrease in CKMT1 expression level could increase the antitumor effect of G2/M cell cycle antagonist-TAX in NSCLC in vitro and in vivo. CONCLUSIONS CKMT1 could interact with CDK4 in mitochondria and regulate the phosphorylated level of CDK4, thus contributing to the proliferation and cell cycle transition of NSCLC cells. And CKMT1 could be a potential target to improve the sensitivity of chemotherapy based on TAX.
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Affiliation(s)
- Mengjie Yang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
- The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Xuecen Wang
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhihua Ye
- Department of Medical Oncology Center, Zhongshan People's Hospital, Zhongshan, Guangdong Province, China
| | - Tingyu Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yuan Meng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Youfa Duan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xuexia Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xin Yue
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Wenbin Deng
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
| | - Ran-Yi Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Zhang S, Mu L, Wang H, Xu X, Jia L, Niu S, Wang Y, Wang P, Li L, Chai J, Li Z, Zhang Y, Zhang H. Quantitative proteomic analysis uncovers protein-expression profiles during gonadotropin-dependent folliculogenesis in mice†. Biol Reprod 2023; 108:479-491. [PMID: 36477298 DOI: 10.1093/biolre/ioac217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 07/14/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
Ovarian follicle is the basic functional unit of female reproduction, and is composed of oocyte and surrounding granulosa cells. In mammals, folliculogenesis strictly rely on gonadotropin regulations to determine the ovulation and the quality of eggs. However, the dynamic changes of protein-expressing profiles in follicles at different developmental stages remain largely unknown. By performing mass-spectrometry-based quantitative proteomic analysis of mouse follicles, we provide a proteomic database (~3000 proteins) that covers three key stages of gonadotropin-dependent folliculogenesis. By combining bioinformatics analysis with in situ expression validation, we showed that our proteomic data well reflected physiological changes during folliculogenesis, which provided potential to predict unknown regulators of folliculogenesis. Additionally, by using the oocyte structural protein zona pellucida protein 2 as the internal control, we showed the possibility of our database to predict the expression dynamics of oocyte-expressing proteins during folliculogenesis. Taken together, we provide a high-coverage proteomic database to study protein-expression dynamics during gonadotropin-dependent folliculogenesis in mammals.
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Affiliation(s)
- Shuo Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Lu Mu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Haoran Wang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Xueqiang Xu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Longzhong Jia
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Shudong Niu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yibo Wang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Peike Wang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Lingyu Li
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Junyi Chai
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Zhen Li
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yan Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Hua Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
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31
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Kim SH, Joung JY, Park WS, Park J, Lee JS, Park B, Hong D. OGT and FLAD1 Genes Had Significant Prognostic Roles in Progressive Pathogenesis in Prostate Cancer. World J Mens Health 2023:41.e30. [PMID: 36792093 DOI: 10.5534/wjmh.220231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/24/2022] [Accepted: 12/14/2022] [Indexed: 02/17/2023] Open
Abstract
PURPOSE This study aimed to identify metabolic genes associated with non-metastatic prostate cancer progression using The Cancer Genome Atlas (TCGA) datasets and validate their prognostic role by assessing patients' immunohistochemical prostatectomy specimens. MATERIALS AND METHODS Several metabolic candidate genes analyzed were highly correlated with cancer progression to biochemical recurrence (BCR) and deaths in 335 patients' genetic information from TCGA datasets. Those candidate genes and their expressions in tissue specimens were validated retrospectively by immunohistochemical analysis of radical prostatectomy specimens collected from 514 consecutive patients with non-metastatic prostate cancer between 2000 and 2015. The Cox proportional-hazards model was used to predict the prognostic role of each candidate gene expression in BCR and survival prognoses with a statistical significance of p-value <0.05. Twenty metabolic genes were identified by own developed software (Targa; https://github.com/cgab-ncc/TarGA), whose median expression levels consistently increased with cancer progression to the BCR and deaths. RESULTS Five metabolic genes (MAT2A, FLAD1, UGDH, OGT, and RRM2) were found to be significantly involved in the overall survival in the TCGA dataset. The immunohistochemical validation and clinicopathological data showed that OGT (hazard ratio [HR], 1.002; 95% confidence interval [CI], 1.001-1.003) and FLAD1 (HR, 1.010; 95% CI, 1.003-1.017) remained significant factors for BCR and cancer-specific survival, respectively, in the multivariate analysis even after adjusting for confounding clinicopathological parameters (p<0.05). CONCLUSIONS OGT and FLAD1 showed significant prognostic factors of disease progression, even after adjustment for confounding clinicopathological parameters in non-metastatic prostate cancer.
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Affiliation(s)
- Sung Han Kim
- Department of Urology, Center for Urological Cancer, National Cancer Center, Goyang, Korea
| | - Jae Young Joung
- Department of Urology, Center for Urological Cancer, National Cancer Center, Goyang, Korea
| | - Weon Seo Park
- Department of Pathology, National Cancer Center, Goyang, Korea
| | - Jongkeun Park
- Department of Medical Informatics, College of Medicine, The Catholic University, Seoul, Korea.,Research Institute, National Cancer Center, Goyang, Korea
| | - Jin Seok Lee
- Department of Medical Informatics, College of Medicine, The Catholic University, Seoul, Korea.,Research Institute, National Cancer Center, Goyang, Korea.,Department of Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Boram Park
- Research Institute, National Cancer Center, Goyang, Korea.,Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Dongwan Hong
- Department of Medical Informatics, College of Medicine, The Catholic University, Seoul, Korea.,Research Institute, National Cancer Center, Goyang, Korea.,Precision Medicine Research Center, College of Medicine, The Catholic University, Seoul, Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University, Seoul, Korea.
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32
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Shen Q, Zhang C, Jiang X, Li J, Liu F, Zhang X, En G, Pang B. Emerging current trends and research focus related to pancreatic cancer metabolism: A bibliometric and visualized analysis. Front Oncol 2022; 12:1009700. [PMID: 36505775 PMCID: PMC9732726 DOI: 10.3389/fonc.2022.1009700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022] Open
Abstract
Background As a malignant digestive system tumor, pancreatic cancer has unique metabolic characteristics. In recent years, the study of pancreatic cancer metabolism is in full swing, which provides a new direction for the treatment of pancreatic cancer patients. However, there is no systematic report of pancreatic cancer metabolism. In this paper, bibliometrics and visualization methods were used to analyze the number of publications, countries/regions, authors, institutions, journals, co-cited references, and keywords of pancreatic cancer metabolism articles, to summarize the research trends and predict research hotspots. Methods We searched, screened and downloaded articles on pancreatic cancer metabolism through the Web of Science Core Collection (WoSCC). Using CiteSpace, VOSviewer and Bibliometrix Package to analyze publications, countries/regions, authors, institutions, journals, co-cited references, and keywords of pancreatic cancer metabolism to identify research trends and predict research hotspots. Results According to the inclusion and exclusion criteria, a total of 5,255 articles were retrieved during the period 1943-2022. The number of publications on pancreatic cancer metabolism is increasing year by year. The United States (n=1602, 30.49%), China (n=1074, 20.44%), and Italy (n=313, 5.96%) are the three countries with the largest number of publications and citations, and there is close cooperation between countries. LI J (n=55) is the most prolific author. FUDAN UNIV (n=348) is the most published institution. CANCERS (n=118), PLOS ONE (n=93), and CANCER RESEARCH (n=80) are the most popular journals in this field. "Nutriment-deficient environment", "cancer chemoprevention" and "targeting cancer stem cell" are the main areas of focus. "immunotherapy", "ferroptosis" and "targeted therapy" are hot keywords in recent years. Taking pancreatic cancer metabolism as an entry point to study the role of traditional Chinese medicine (TCM) mainly focuses on curcumin and resveratrol, lack of broader and deeper research on TCM. Conclusions The number of publications on pancreatic cancer metabolism has generally increased, and scholars have generally paid more attention to this field. "immunotherapy", "ferroptosis" and "targeted therapy" are the current research hotspots. The in-depth study of pancreatic cancer metabolism will provide new ideas for the treatment of pancreatic cancer.
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Affiliation(s)
- Qian Shen
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chuanlong Zhang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaochen Jiang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junchen Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fudong Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiyuan Zhang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ge’er En
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bo Pang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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33
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Negi S, Chaudhuri A, Kumar DN, Dehari D, Singh S, Agrawal AK. Nanotherapeutics in autophagy: a paradigm shift in cancer treatment. Drug Deliv Transl Res 2022; 12:2589-2612. [PMID: 35149969 DOI: 10.1007/s13346-022-01125-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2022] [Indexed: 12/15/2022]
Abstract
Autophagy is a catabolic process in which an organism responds to its nutrient or metabolic emergencies. It involves the degradation of cytoplasmic proteins and organelles by forming double-membrane vesicles called "autophagosomes." They sequester cargoes, leading them to degradation in the lysosomes. Although autophagy acts as a protective mechanism for maintaining homeostasis through cellular recycling, it is ostensibly a cause of certain cancers, but a cure for others. In other words, insufficient autophagy, due to genetic or cellular dysfunctions, can lead to tumorigenesis. However, many autophagy modulators are developed for cancer therapy. Diverse nanoparticles have been documented to induce autophagy. Also, the highly stable nanoparticles show blockage to autophagic flux. In this review, we revealed a general mechanism by which autophagy can be induced or blocked via nanoparticles as well as several studies recently performed to prove the stated fact. In addition, we have also elucidated the paradoxical roles of autophagy in cancer and how their differential role at different stages of various cancers can affect its treatment outcomes. And finally, we summarize the breakthroughs in cancer disease treatments by using metallic, polymeric, and liposomal nanoparticles as potent autophagy modulators.
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Affiliation(s)
- Shloka Negi
- Department of Pharmaceutical Eng. & Technology, Indian Institute of Technology (BHU), Varanasi, 221005, UP, India
| | - Aiswarya Chaudhuri
- Department of Pharmaceutical Eng. & Technology, Indian Institute of Technology (BHU), Varanasi, 221005, UP, India
| | - Dulla Naveen Kumar
- Department of Pharmaceutical Eng. & Technology, Indian Institute of Technology (BHU), Varanasi, 221005, UP, India
| | - Deepa Dehari
- Department of Pharmaceutical Eng. & Technology, Indian Institute of Technology (BHU), Varanasi, 221005, UP, India
| | - Sanjay Singh
- Department of Pharmaceutical Eng. & Technology, Indian Institute of Technology (BHU), Varanasi, 221005, UP, India
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Eng. & Technology, Indian Institute of Technology (BHU), Varanasi, 221005, UP, India.
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34
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Culpan M, Iplikci A, Kir G, Cecikoglu GE, Atis G, Yildirim A. The prognostic impact of tumor necrosis in non-muscle invasive bladder cancer. Rev Assoc Med Bras (1992) 2022; 68:1587-1592. [DOI: 10.1590/1806-9282.20220812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/01/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
| | | | - Gozde Kir
- Istanbul Medeniyet University, Turkey
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35
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Kiani Shahvandi M, Soltani M, Moradi Kashkooli F, Saboury B, Rahmim A. Spatiotemporal multi-scale modeling of radiopharmaceutical distributions in vascularized solid tumors. Sci Rep 2022; 12:14582. [PMID: 36028541 PMCID: PMC9418261 DOI: 10.1038/s41598-022-18723-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 08/18/2022] [Indexed: 11/09/2022] Open
Abstract
We present comprehensive mathematical modeling of radiopharmaceutical spatiotemporal distributions within vascularized solid tumors. The novelty of the presented model is at mathematical level. From the mathematical viewpoint, we provide a general modeling framework for the process of radiopharmaceutical distribution in the tumor microenvironment to enable an analysis of the effect of various tumor-related parameters on the distribution of different radiopharmaceuticals. We argue that partial differential equations (PDEs), beyond conventional methods, including ODE-based kinetic compartment modeling, can be used to evaluate radiopharmaceutical distribution in both time and space. In addition, we consider the spatially-variable dynamic structure of tumor microvascular networks to simulate blood flow distribution. To examine the robustness of the model, the effects of microvessel density (MVD) and tumor size, as two important factors in tumor prognosis, on the radiopharmaceutical distribution within the tumor are investigated over time (in the present work, we focus on the radiopharmaceutical [18F]FDG, yet the framework is broadly applicable to radiopharmaceuticals). Results demonstrate that the maximum total uptake of [18F]FDG at all time frames occurs in the tumor area due to the high capillary permeability and lack of a functional lymphatic system. As the MVD of networks increases, the mean total uptake in the tumor is also enhanced, where the rate of diffusion from vessel to tissue has the highest contribution and the rate of convection transport has the lowest contribution. The results of this study can be used to better investigate various phenomena and bridge a gap among cancer biology, mathematical oncology, medical physics, and radiology.
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Affiliation(s)
| | - M Soltani
- Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran, Iran. .,Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON, Canada. .,Centre for Biotechnology and Bioengineering (CBB), University of Waterloo, Waterloo, ON, Canada. .,Advanced Bioengineering Initiative Center, Multidisciplinary International Complex, K. N. Toosi University of Technology, Tehran, Iran.
| | | | - Babak Saboury
- Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA.,Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Arman Rahmim
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.,Departments of Radiology and Physics, University of British Columbia, Vancouver, BC, Canada
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36
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Bronikowska I, Swietochowska E, Morawski R, Sowa P, Czecior E. Concentration of hypoxia-inducible factor-1, glucose transporter 1 and vascular endothelial growth factor in tissue samples and serum in patients with primary laryngeal carcinoma. Acta Otolaryngol 2022; 142:532-536. [PMID: 35724238 DOI: 10.1080/00016489.2022.2085885] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
BACKGROUND Markers of tumorigenesis are essential factors which may play a major role in the early detection of head and neck carcinoma. AIMS/OBJECTIVES To assess concentration of HIF-1, GLUT1 and VEGF in tissue samples and blood serum and its correlation to the tumour size, nodal disease, pathologic differentiation and patients' data. MATERIAL AND METHODS Fifty-two patients diagnosed with laryngeal carcinoma stage I-IV in which concentration of HIF-1, GLUT1 and VEGF was assessed in tissue samples and blood serum using immunoassay method. RESULTS HIF-1α, GLUT1, VEGF concentration was significantly higher in cancer tissue samples than in normal tissue (p < .001) and benign laryngeal lesions. Serum levels of the factors were significantly lower in the control group. Statistically significant difference regarding tumour size was found between T2 and T4 stages in HIF-1α concentration in cancer samples and serum. CONCLUSIONS The results show that high concentration of HIF-1α, GLUT1 and VEGF might be suggestive of carcinogenic process when diagnosing patients with laryngeal lesions and could promote early detection of malignancy. SIGNIFICANCE The results of this study show importance of biochemical assessment in malignant tumours which may affect clinical decisions.
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Affiliation(s)
- Izabela Bronikowska
- Department of Otorhinolaryngology Medical, University of Silesia, Zabrze, Poland
| | - Elzbieta Swietochowska
- Department of Medical and Molecular Biology Medical, University of Silesia, Zabrze, Poland
| | - Robert Morawski
- Department of Otorhinolaryngology Medical, University of Silesia, Zabrze, Poland
| | - Pawel Sowa
- Department of Otorhinolaryngology Medical, University of Silesia, Zabrze, Poland
| | - Eugeniusz Czecior
- Department of Otorhinolaryngology Medical, University of Silesia, Zabrze, Poland
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37
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Roman M, Hwang E, Sweet-Cordero EA. Synthetic Vulnerabilities in the KRAS Pathway. Cancers (Basel) 2022; 14:cancers14122837. [PMID: 35740503 PMCID: PMC9221492 DOI: 10.3390/cancers14122837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/03/2022] [Accepted: 06/05/2022] [Indexed: 02/06/2023] Open
Abstract
Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.
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38
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Islam MS, Jesmin. Association of Hypoxia-Inducible Factor 1α Gene Polymorphisms With Breast Cancer Susceptibility: A Meta-Analysis. JCO Glob Oncol 2022; 8:e2100399. [PMID: 35507894 PMCID: PMC9126528 DOI: 10.1200/go.21.00399] [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] [Indexed: 12/09/2022] Open
Abstract
PURPOSE Overexpression of the hypoxia-inducible factor 1α (HIF1A) gene is significantly associated with different types of cancers, including breast cancer. In this study, the effects of single-nucleotide polymorphisms rs11549465, rs11549467, and rs2057482 of the HIF1A gene and their association with breast cancer were systematically investigated through meta-analysis. MATERIALS AND METHODS After a systematic review, nine case-control studies of the HIF1A rs11549465 C/T polymorphism, six case-control studies of the HIF1A rs11549467 G/A polymorphism, and one case-control study of the HIF1A rs2057482 C/T polymorphism were included in this meta-analysis. The summary pooled odds ratios with 95% CIs were evaluated to detect the relationship between HIF1A polymorphisms and breast cancer susceptibility. RESULTS Subgroup-stratified analyses showed that the T and TT genotypes of the HIF1A rs11549465 C/T polymorphism were significantly associated with increased breast cancer risk in the Asian population under three genetic models (allele, homozygous, and recessive). HIF1A rs11549467 G/A analyses indicated that the A and AA genotypes were significantly associated with increased breast cancer risk in the Asian population under allele and dominant models. However, no association with breast cancer was observed in the White population for the HIF1A rs11549465 C/T and rs11549467 G/A polymorphisms. In addition, the HIF1A rs2057482 C/T polymorphism showed no association with breast cancer under any genetic models or by ethnicity-stratified analyses. CONCLUSION The results of this meta-analysis suggested that the HIF1A rs11549465 C/T and rs1154946 G/A polymorphisms were significantly associated with increased breast cancer risk in the Asian population, but no associations were found in the White population. Thus, HIF1A could be an important biomarker for population-based breast cancer screening.
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Affiliation(s)
- Md. Shihabul Islam
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, Bangladesh
| | - Jesmin
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh
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39
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Thévenod F, Schreiber T, Lee WK. Renal hypoxia-HIF-PHD-EPO signaling in transition metal nephrotoxicity: friend or foe? Arch Toxicol 2022; 96:1573-1607. [PMID: 35445830 PMCID: PMC9095554 DOI: 10.1007/s00204-022-03285-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/14/2022] [Indexed: 12/18/2022]
Abstract
The kidney is the main organ that senses changes in systemic oxygen tension, but it is also the key detoxification, transit and excretion site of transition metals (TMs). Pivotal to oxygen sensing are prolyl-hydroxylases (PHDs), which hydroxylate specific residues in hypoxia-inducible factors (HIFs), key transcription factors that orchestrate responses to hypoxia, such as induction of erythropoietin (EPO). The essential TM ion Fe is a key component and regulator of the hypoxia–PHD–HIF–EPO (HPHE) signaling axis, which governs erythropoiesis, angiogenesis, anaerobic metabolism, adaptation, survival and proliferation, and hence cell and body homeostasis. However, inadequate concentrations of essential TMs or entry of non-essential TMs in organisms cause toxicity and disrupt health. Non-essential TMs are toxic because they enter cells and displace essential TMs by ionic and molecular mimicry, e. g. in metalloproteins. Here, we review the molecular mechanisms of HPHE interactions with TMs (Fe, Co, Ni, Cd, Cr, and Pt) as well as their implications in renal physiology, pathophysiology and toxicology. Some TMs, such as Fe and Co, may activate renal HPHE signaling, which may be beneficial under some circumstances, for example, by mitigating renal injuries from other causes, but may also promote pathologies, such as renal cancer development and metastasis. Yet some other TMs appear to disrupt renal HPHE signaling, contributing to the complex picture of TM (nephro-)toxicity. Strikingly, despite a wealth of literature on the topic, current knowledge lacks a deeper molecular understanding of TM interaction with HPHE signaling, in particular in the kidney. This precludes rationale preventive and therapeutic approaches to TM nephrotoxicity, although recently activators of HPHE signaling have become available for therapy.
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Affiliation(s)
- Frank Thévenod
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Stockumer Strasse 12, 58453, Witten, Germany.
| | - Timm Schreiber
- Institute for Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Stockumer Strasse 12, 58453, Witten, Germany
| | - Wing-Kee Lee
- Physiology and Pathophysiology of Cells and Membranes, Medical School EWL, Bielefeld University, R.1 B2-13, Morgenbreede 1, 33615 Bielefeld, Germany
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40
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Seo J, Yun JE, Kim SJ, Chun YS. Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment. Pflugers Arch 2022; 474:591-601. [PMID: 35348849 DOI: 10.1007/s00424-022-02683-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/10/2022] [Accepted: 03/12/2022] [Indexed: 10/18/2022]
Abstract
Cancer cells rewire metabolic processes to adapt to the nutrient- and oxygen-deprived tumour microenvironment, thereby promoting their proliferation and metastasis. Previous research has shown that modifying glucose metabolism, the Warburg effect, makes glycolytic cancer cells more invasive and aggressive. Lipid metabolism has also been receiving attention because lipids function as energy sources and signalling molecules. Because obesity is a risk factor for various cancer types, targeting lipid metabolism may be a promising cancer therapy. Here, we review the lipid metabolic reprogramming in cancer cells mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is the master transcription factor for tumour growth and metastasis by transactivating genes related to proliferation, survival, angiogenesis, invasion, and metabolism. The glucose metabolic shift (the Warburg effect) is mediated by HIF-1. Recent research on HIF-1-related lipid metabolic reprogramming in cancer has confirmed that HIF-1 also modifies lipid accumulation, β-oxidation, and lipolysis in cancer, triggering its progression. Therefore, targeting lipid metabolic alterations by HIF-1 has therapeutic potential for cancer. We summarize the role of the lipid metabolic shift mediated by HIF-1 in cancer and its putative applications for cancer therapy.
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Affiliation(s)
- Jieun Seo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Faculty of Engineering, Yokohama National University, Yokohama, 240-8501, Japan.,Kanagawa Institute of Industrial Science and Technology, Kawasaki, 213-0012, Japan
| | - Jeong-Eun Yun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Sung Joon Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea.,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Yang-Sook Chun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea. .,Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea. .,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
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Ryniawec JM, Coope MR, Loertscher E, Bageerathan V, de Oliveira Pessoa D, Warfel NA, Cress AE, Padi M, Rogers GC. GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors. Diagnostics (Basel) 2022; 12:diagnostics12030676. [PMID: 35328229 PMCID: PMC8946944 DOI: 10.3390/diagnostics12030676] [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: 02/12/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 01/17/2023] Open
Abstract
The microenvironment of solid tumors is dynamic and frequently contains pockets of low oxygen levels (hypoxia) surrounded by oxygenated tissue. Indeed, a compromised vasculature is a hallmark of the tumor microenvironment, creating both spatial gradients and temporal variability in oxygen availability. Notably, hypoxia associates with increased metastasis and poor survival in patients. Therefore, to aid therapeutic decisions and better understand hypoxia’s role in cancer progression, it is critical to identify endogenous biomarkers of hypoxia to spatially phenotype oncogenic lesions in human tissue, whether precancerous, benign, or malignant. Here, we characterize the glucose transporter GLUT3/SLC2A3 as a biomarker of hypoxic prostate epithelial cells and prostate tumors. Transcriptomic analyses of non-tumorigenic, immortalized prostate epithelial cells revealed a highly significant increase in GLUT3 expression under hypoxia. Additionally, GLUT3 protein increased 2.4-fold in cultured hypoxic prostate cell lines and was upregulated within hypoxic regions of xenograft tumors, including two patient-derived xenografts (PDX). Finally, GLUT3 out-performs other established hypoxia markers; GLUT3 staining in PDX specimens detects 2.6–8.3 times more tumor area compared to a mixture of GLUT1 and CA9 antibodies. Therefore, given the heterogeneous nature of tumors, we propose adding GLUT3 to immunostaining panels when trying to detect hypoxic regions in prostate samples.
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Affiliation(s)
- John M. Ryniawec
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Matthew R. Coope
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Emily Loertscher
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Vignesh Bageerathan
- Biostatistics and Bioinformatics Shared Resource, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA; (V.B.); (D.d.O.P.)
| | - Diogo de Oliveira Pessoa
- Biostatistics and Bioinformatics Shared Resource, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA; (V.B.); (D.d.O.P.)
| | - Noel A. Warfel
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
| | - Anne E. Cress
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
- Correspondence: (A.E.C.); (M.P.); (G.C.R.)
| | - Megha Padi
- Department of Molecular and Cellular Biology, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA
- Correspondence: (A.E.C.); (M.P.); (G.C.R.)
| | - Gregory C. Rogers
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA; (J.M.R.); (M.R.C.); (E.L.); (N.A.W.)
- Correspondence: (A.E.C.); (M.P.); (G.C.R.)
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Stimuli-controllable iron oxide nanoparticle assemblies: Design, manipulation and bio-applications. J Control Release 2022; 345:231-274. [DOI: 10.1016/j.jconrel.2022.03.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/11/2022] [Accepted: 03/12/2022] [Indexed: 02/07/2023]
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Zhang F, Liang J, Feng D, Liu S, Wu J, Tang Y, Liu Z, Lu Y, Wang X, Wei X. Integrated Analysis of Energy Metabolism Signature-Identified Distinct Subtypes of Bladder Urothelial Carcinoma. Front Cell Dev Biol 2022; 10:814735. [PMID: 35281080 PMCID: PMC8905247 DOI: 10.3389/fcell.2022.814735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 02/03/2022] [Indexed: 01/08/2023] Open
Abstract
Background: Bladder urothelial carcinoma (BLCA) is the most common type of bladder cancer. In this study, the correlation between the metabolic status and the outcome of patients with BLCA was evaluated using data from the Cancer Genome Atlas and Gene Expression Omnibus datasets. Methods: The clinical and transcriptomic data of patients with BLCA were downloaded from the Cancer Genome Atlas and cBioPortal datasets, and energy metabolism-related gene sets were obtained from the Molecular Signature Database. A consensus clustering algorithm was then conducted to classify the patients into two clusters. Tumor prognosis, clinicopathological features, mutations, functional analysis, ferroptosis status analysis, immune infiltration, immune checkpoint-related gene expression level, chemotherapy resistance, and tumor stem cells were analyzed between clusters. An energy metabolism-related signature was further developed and verified using data from cBioPortal datasets. Results: Two clusters (C1 and C2) were identified using a consensus clustering algorithm based on an energy metabolism-related signature. The patients with subtype C1 had more metabolism-related pathways, different ferroptosis status, higher cancer stem cell scores, higher chemotherapy resistance, and better prognosis. Subtype C2 was characterized by an increased number of advanced BLCA cases and immune-related pathways. Higher immune and stromal scores were also observed for the C2 subtype. A signature containing 16 energy metabolism-related genes was then identified, which can accurately predict the prognosis of patients with BLCA. Conclusion: We found that the energy metabolism-associated subtypes of BLCA are closely related to the immune microenvironment, immune checkpoint-related gene expression, ferroptosis status, CSCs, chemotherapy resistance, prognosis, and progression of BLCA patients. The established energy metabolism-related gene signature was able to predict survival in patients with BLCA.
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Affiliation(s)
- Fan Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jiayu Liang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Shengzhuo Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jiapei Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongquan Tang
- Department of Pediatric Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhihong Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yiping Lu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Xianding Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xianding Wang, ; Xin Wei,
| | - Xin Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xianding Wang, ; Xin Wei,
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Kushchayeva Y, Kushchayev S, Jensen K, Brown RJ. Impaired Glucose Metabolism, Anti-Diabetes Medications, and Risk of Thyroid Cancer. Cancers (Basel) 2022; 14:cancers14030555. [PMID: 35158824 PMCID: PMC8833385 DOI: 10.3390/cancers14030555] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary An epidemiologic link exists between obesity, insulin resistance, diabetes, and some cancers, such as breast cancer and colon cancer. The prevalence of obesity and diabetes is increasing, and additional epidemiologic data suggest that there may be a link between obesity and risk of thyroid abnormalities. Factors that may link obesity and diabetes with thyroid proliferative disorders include elevated circulating levels of insulin, increased body fat, high blood sugars, and exogenous insulin use. However, mechanisms underlying associations of obesity, diabetes, and thyroid proliferative disorders are not yet fully understood. The present manuscript reviews and summarizes current evidence of mechanisms and epidemiologic associations of obesity, insulin resistance, and use of anti-diabetes medications with benign and malignant proliferative disorders of the thyroid. Abstract The prevalence of obesity is progressively increasing along with the potential high risk for insulin resistance and development of type 2 diabetes mellitus. Obesity is associated with increased risk of many malignancies, and hyperinsulinemia has been proposed to be a link between obesity and cancer development. The incidence of thyroid cancer is also increasing, making this cancer the most common endocrine malignancy. There is some evidence of associations between obesity, insulin resistance and/or diabetes with thyroid proliferative disorders, including thyroid cancer. However, the etiology of such an association has not been fully elucidated. The goal of the present work is to review the current knowledge on crosstalk between thyroid and glucose metabolic pathways and the effects of obesity, insulin resistance, diabetes, and anti-hyperglycemic medications on the risk of thyroid cancer development.
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Affiliation(s)
- Yevgeniya Kushchayeva
- Diabetes and Endocrinology Center, University of South Florida, Tampa, FL 33612, USA
- Correspondence:
| | - Sergiy Kushchayev
- Department of Radiology, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Kirk Jensen
- F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA;
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;
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Said YM, El-Gamel NEA, Ali SA, Mohamed AF. Evaluation of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Conditioning Medium (hWJ-MSCs-CM) or Scorpion Venom Breast Cancer Cell Line In Vitro. J Gastrointest Cancer 2022; 53:888-901. [PMID: 34988906 DOI: 10.1007/s12029-021-00762-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE The present study aimed to evaluate the anticancer potential of Egyptian scorpion Leiurus quinquestriatus venom (ScV) or human Wharton's jelly-derived mesenchymal stem cells conditioning medium (hWJ-MSCs-CM)/CM against breast cancer (MCF-7) cell line as an alternative effective cancer biotherapy. METHODS Venom (ScV) toxicity was performed recording concentration-dependent viability % and ScV IC50 value was in the order of 100 μg/ml. MCF-7 were treated with hWJ-MSCs-CM used as (25%, 50%, and 75% ml) or the IC50 of ScV. Apoptotic activity was traced via evaluation the apoptotic (Bax, Casp-3, and Casp-9) and anti-apoptotic genes (Bcl2, ALDOA, and PKM2) profile. RESULTS Both Bax and Casp-3 showed a significant upregulation while anti-apoptotic genes were significantly downregulated. In the meantime, Casp-3 and Casp-9 protein were monitored using ELISA, and their level was less than in control. Additionally, MCF-7 apoptosis was monitored using flow cytometry recording a significant DNA accumulation in the G0-G1 and S phases in case of cell treatment with ScV or CM75% ml and 50% ml. Also, there was a significant total necrotic cells % compared with control cells, and total apoptosis under the effect of ScV or CM75% ml was significantly elevated than rest of treatment. CONCLUSION Apoptosis induction was both dose- and time-dependent for hWJ-MSCs-CM and ScV. According to the present study and other studies, there is an ample evidence that hWJ-MSCs-CM and the venom IC50 abolish tumor growth.
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Affiliation(s)
| | - Nadia E A El-Gamel
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
| | - Said A Ali
- Department of Biophysics, Faculty of Science, Cairo University, Giza, Egypt
| | - Aly Fahmy Mohamed
- The International Center for Advanced Researches (ICTAR), Giza, Egypt
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Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature 2022; 608:421-428. [PMID: 35922508 PMCID: PMC9365697 DOI: 10.1038/s41586-022-05030-3] [Citation(s) in RCA: 137] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/28/2022] [Indexed: 02/05/2023]
Abstract
Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
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Güzel-Akdemir Ö, Demir-Yazıcı K, Vullo D, Supuran CT, Akdemir A. New Pyridinium Salt Derivatives of 2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5- sulfonamide as Selective Inhibitors of Tumour-Related Human Carbonic Anhydrase Isoforms IX and XII. Anticancer Agents Med Chem 2022; 22:2637-2646. [PMID: 35135455 DOI: 10.2174/1871520622666220207092123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/24/2021] [Accepted: 12/20/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The positively charged membrane impermeant sulfonamides were evaluated as a remarkable class of carbonic anhydrase inhibitors (CAIs) previously. Without affecting the human carbonic anhydrase (hCA), cytosolic isoforms hCA I and II, inhibition of two membrane-associated isoforms hCA IX and XII especially overexpressed in hypoxic tumour cells, makes the pyridinium salt derivatives potent promising therapeutic agents. OBJECTIVE A novel series of tri, tetra, and cyclo-substituted pyridinium salt derivatives of the lead compound 2- (hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide has been prepared by using sixteen different pyrylium salts, for the search of selective inhibitors of transmembrane tumour-associated human carbonic anhydrase hCA IX and XII. METHODS Molecular modeling studies were carried out to understand and rationalize the in vitro enzyme inhibition data. RESULTS Six of the new compounds showed good inhibitory profiles with low nanomolar range (< 100 nM) against hCA IX/XII, and compound 5 showed excellent potency with Ki values lower than 10 nM. In addition, molecular modelling studies have presented the possible binding modes of the ligands. CONCLUSION Most of the compounds displayed potent inhibitory activity against the tumor-associated hCA IX and XII in the low nanomolar range and selectivity over the off-targeted isoforms hCA I and II. Due to their cationic structure and membrane-impermeant behavior, it is also expected to maximize the selectivity over cytosolic isoforms hCA I/II while inhibiting tumor overexpressed isoforms hCA XI/XII of new compounds in in vivo conditions.
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Affiliation(s)
- Özlen Güzel-Akdemir
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Kübra Demir-Yazıcı
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Daniela Vullo
- Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Florence, Italy
| | - Claudiu T Supuran
- Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Florence, Italy
| | - Atilla Akdemir
- Computer-aided Drug Discovery Laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey
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Luo J, Sun P, Zhang X, Lin G, Xin Q, Niu Y, Chen Y, Xu N, Zhang Y, Xie W. Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway. Int J Mol Sci 2021; 22:ijms222413336. [PMID: 34948132 PMCID: PMC8704642 DOI: 10.3390/ijms222413336] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 12/30/2022] Open
Abstract
The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hypoxia, and demonstrated that CANA could significantly inhibit hypoxia-induced metastasis, angiogenesis, and metabolic reprogramming in HCC. At the molecular level, this was accompanied by a reduction in VEGF expression level, as well as a reduction in the epithelial-to-mesenchymal transition (EMT)-related proteins and glycolysis-related proteins. Next, we focused our study particularly on the modulation of HIF-1α by CANA, which revealed that CANA decreased HIF-1α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the AKT/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CANA. Thus, it can be concluded that CANA decreased metastasis, angiogenesis, and metabolic reprogramming in HCC by inhibiting HIF-1α protein accumulation, probably by targeting the AKT/mTOR pathway. Based on our results, we propose that CANA should be evaluated as a new treatment modality for liver cancer.
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MESH Headings
- Animals
- Canagliflozin/pharmacology
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Hypoxia/drug effects
- Cell Hypoxia/genetics
- Glycolysis/drug effects
- Hep G2 Cells
- Human Umbilical Vein Endothelial Cells
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Mice, SCID
- Neoplasm Metastasis
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Signal Transduction/drug effects
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Jingyi Luo
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Pengbo Sun
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Xun Zhang
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Guanglan Lin
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Qilei Xin
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Yaoyun Niu
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yang Chen
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Naihan Xu
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yaou Zhang
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Weidong Xie
- State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; (J.L.); (P.S.); (X.Z.); (G.L.); (Q.X.); (Y.N.); (Y.C.); (N.X.); (Y.Z.)
- Shenzhen Key Lab of Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Department of Chemistry, Tsinghua University, Beijing 100084, China
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Correspondence:
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Abd El-Aziz YS, Leck LYW, Jansson PJ, Sahni S. Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:6152. [PMID: 34944772 PMCID: PMC8699656 DOI: 10.3390/cancers13246152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC.
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Affiliation(s)
- Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
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Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov 2021; 21:141-162. [PMID: 34862480 PMCID: PMC8641543 DOI: 10.1038/s41573-021-00339-6] [Citation(s) in RCA: 655] [Impact Index Per Article: 163.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2021] [Indexed: 12/23/2022]
Abstract
One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.
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Affiliation(s)
| | | | | | - Chi V Dang
- The Wistar Institute Philadelphia, Philadelphia, PA, USA. .,Ludwig Institute for Cancer Research New York, New York, NY, USA.
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