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Chen F, Xue Y, Zhang W, Zhou H, Zhou Z, Chen T, YinWang E, Li H, Ye Z, Gao J, Wang S. The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy. Cancer Metastasis Rev 2024; 43:1419-1443. [PMID: 39307891 PMCID: PMC11554835 DOI: 10.1007/s10555-024-10211-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 09/08/2024] [Indexed: 11/05/2024]
Abstract
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.
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Affiliation(s)
- Fanglu Chen
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yucheng Xue
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenkan Zhang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hao Zhou
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhiyi Zhou
- The First People's Hospital of Yuhang District, Hangzhou, Zhejiang, China
| | - Tao Chen
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Eloy YinWang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hengyuan Li
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhaoming Ye
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China.
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Shengdong Wang
- Department of Orthopedics, Musculoskeletal Tumor Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, P.R. China.
- Institute of Orthopedic Research, Zhejiang University, Hangzhou, 310009, P.R. China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
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Benito-Martín A, Jasiulionis MG, García-Silva S. Extracellular vesicles and melanoma: New perspectives on tumor microenvironment and metastasis. Front Cell Dev Biol 2023; 10:1061982. [PMID: 36704194 PMCID: PMC9871288 DOI: 10.3389/fcell.2022.1061982] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023] Open
Abstract
Secreted extracellular vesicles (EVs) are lipid bilayer particles without functional nucleus naturally released from cells which constitute an intercellular communication system. There is a broad spectrum of vesicles shed by cells based on their physical properties such as size (small EVs and large EVs), biogenesis, cargo and functions, which provide an increasingly heterogenous landscape. In addition, they are involved in multiple physiological and pathological processes. In cancer, EV release is opted by tumor cells as a beneficial process for tumor progression. Cutaneous melanoma is a cancer that originates from the melanocyte lineage and shows a favorable prognosis at early stages. However, when melanoma cells acquire invasive capacity, it constitutes the most aggressive and deadly skin cancer. In this context, extracellular vesicles have been shown their relevance in facilitating melanoma progression through the modulation of the microenvironment and metastatic spreading. In agreement with the melanosome secretory capacity of melanocytes, melanoma cells display an enhanced EV shedding activity that has contributed to the utility of melanoma models for unravelling EV cargo and functions within a cancer scenario. In this review, we provide an in-depth overview of the characteristics of melanoma-derived EVs and their role in melanoma progression highlighting key advances and remaining open questions in the field.
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Affiliation(s)
- Alberto Benito-Martín
- Facultad de Medicina, Unidad de Investigación Biomédica, Universidad Alfonso X El Sabio (UAX), Villanueva de la Cañada, Spain,*Correspondence: Alberto Benito-Martín, ; Miriam Galvonas Jasiulionis, ; Susana García-Silva,
| | - Miriam Galvonas Jasiulionis
- Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil,*Correspondence: Alberto Benito-Martín, ; Miriam Galvonas Jasiulionis, ; Susana García-Silva,
| | - Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain,*Correspondence: Alberto Benito-Martín, ; Miriam Galvonas Jasiulionis, ; Susana García-Silva,
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Park SS, Jeong H, Andreazza AC. Circulating cell-free mitochondrial DNA in brain health and disease: A systematic review and meta-analysis. World J Biol Psychiatry 2022; 23:87-102. [PMID: 34096821 DOI: 10.1080/15622975.2021.1938214] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Circulating cell-free mitochondrial DNA (ccf-mtDNA) are detectable fragments of mtDNA released from the cell as a result of mitochondrial dysfunction or apoptosis. The brain is one of the most energy demanding organs in the human body, and many neuropsychiatric and non-psychiatric neurological diseases have mitochondrial dysfunction associated with disease pathophysiology. Thus, we aimed to assess ccf-mtDNA as a potential biomarker for brain diseases. METHODS We conducted a systematic review and meta-analyses of studies that examined peripheral and/or cerebrospinal fluid (CSF) ccf-mtDNA relevant to neuropsychiatric conditions, which we define as disorders of affect, behaviour and mood, and non-psychiatric neurological diseases, which consist of neurological diseases not related to psychiatry including neurodegenerative diseases. RESULTS The results of the sensitivity analysis investigating the levels of peripheral ccf-mtDNA in neuropsychiatric studies showed no significant difference between cases and controls (Z = 1.57; p = 0.12), whereas the results of the sensitivity analysis investigating the levels of CSF ccf-mtDNA in non-psychiatric neurological diseases showed a decreasing trend in cases compared with controls (Z = 2.32; p = 0.02). Interestingly, the results indicate an overall mitochondrial stress associated mainly with non-psychiatric neurological diseases. CONCLUSIONS Our study supports the involvement of mitochondrial stress, here defined as ccf-mtDNA, in brain diseases and encourage further investigation of ccf-mtDNA among patients with brain diseases.
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Affiliation(s)
- Sarah Sohyun Park
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada.,Women's College Research Institute, Women's College Hospital, Toronto, Canada
| | - Hyunjin Jeong
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.,Centre for Addiction and Mental Health, Toronto, Canada
| | - Ana C Andreazza
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.,Centre for Addiction and Mental Health, Toronto, Canada.,Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Canada
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Sreedhar A, Aguilera-Aguirre L, Singh KK. Mitochondria in skin health, aging, and disease. Cell Death Dis 2020; 11:444. [PMID: 32518230 PMCID: PMC7283348 DOI: 10.1038/s41419-020-2649-z] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/22/2020] [Accepted: 05/25/2020] [Indexed: 02/08/2023]
Abstract
The skin is a high turnover organ, and its constant renewal depends on the rapid proliferation of its progenitor cells. The energy requirement for these metabolically active cells is met by mitochondrial respiration, an ATP generating process driven by a series of protein complexes collectively known as the electron transport chain (ETC) that is located on the inner membrane of the mitochondria. However, reactive oxygen species (ROS) like superoxide, singlet oxygen, peroxides are inevitably produced during respiration and disrupt macromolecular and cellular structures if not quenched by the antioxidant system. The oxidative damage caused by mitochondrial ROS production has been established as the molecular basis of multiple pathophysiological conditions, including aging and cancer. Not surprisingly, the mitochondria are the primary organelle affected during chronological and UV-induced skin aging, the phenotypic manifestations of which are the direct consequence of mitochondrial dysfunction. Also, deletions and other aberrations in the mitochondrial DNA (mtDNA) are frequent in photo-aged skin and skin cancer lesions. Recent studies have revealed a more innate role of the mitochondria in maintaining skin homeostasis and pigmentation, which are affected when the essential mitochondrial functions are impaired. Some common and rare skin disorders have a mitochondrial involvement and include dermal manifestations of primary mitochondrial diseases as well as congenital skin diseases caused by damaged mitochondria. With studies increasingly supporting the close association between mitochondria and skin health, its therapeutic targeting in the skin-either via an ATP production boost or free radical scavenging-has gained attention from clinicians and aestheticians alike. Numerous bioactive compounds have been identified that improve mitochondrial functions and have proved effective against aged and diseased skin. In this review, we discuss the essential role of mitochondria in regulating normal and abnormal skin physiology and the possibility of targeting this organelle in various skin disorders.
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Affiliation(s)
| | | | - Keshav K Singh
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
- Integartive Center For Aging Research and O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
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PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes-Implications for UV-Induced DNA Repair and Photocarcinogenesis. Cancers (Basel) 2019; 12:cancers12010005. [PMID: 31861350 PMCID: PMC7016756 DOI: 10.3390/cancers12010005] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/07/2019] [Accepted: 12/10/2019] [Indexed: 01/02/2023] Open
Abstract
Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM.
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Weerts MJA, Timmermans EC, van de Stolpe A, Vossen RHAM, Anvar SY, Foekens JA, Sleijfer S, Martens JWM. Tumor-Specific Mitochondrial DNA Variants Are Rarely Detected in Cell-Free DNA. Neoplasia 2018; 20:687-696. [PMID: 29842994 PMCID: PMC6030393 DOI: 10.1016/j.neo.2018.05.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/07/2018] [Accepted: 05/08/2018] [Indexed: 12/14/2022] Open
Abstract
The use of blood-circulating cell-free DNA (cfDNA) as a “liquid biopsy” in oncology is being explored for its potential as a cancer biomarker. Mitochondria contain their own circular genomic entity (mitochondrial DNA, mtDNA), up to even thousands of copies per cell. The mutation rate of mtDNA is several orders of magnitude higher than that of the nuclear DNA. Tumor-specific variants have been identified in tumors along the entire mtDNA, and their number varies among and within tumors. The high mtDNA copy number per cell and the high mtDNA mutation rate make it worthwhile to explore the potential of tumor-specific cf-mtDNA variants as cancer marker in the blood of cancer patients. We used single-molecule real-time (SMRT) sequencing to profile the entire mtDNA of 19 tissue specimens (primary tumor and/or metastatic sites, and tumor-adjacent normal tissue) and 9 cfDNA samples, originating from 8 cancer patients (5 breast, 3 colon). For each patient, tumor-specific mtDNA variants were detected and traced in cfDNA by SMRT sequencing and/or digital PCR to explore their feasibility as cancer biomarker. As a reference, we measured other blood-circulating biomarkers for these patients, including driver mutations in nuclear-encoded cfDNA and cancer-antigen levels or circulating tumor cells. Four of the 24 (17%) tumor-specific mtDNA variants were detected in cfDNA, however at much lower allele frequencies compared to mutations in nuclear-encoded driver genes in the same samples. Also, extensive heterogeneity was observed among the heteroplasmic mtDNA variants present in an individual. We conclude that there is limited value in tracing tumor-specific mtDNA variants in blood-circulating cfDNA with the current methods available.
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Affiliation(s)
- M J A Weerts
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - E C Timmermans
- Philips Research Laboratories, High Tech Campus 11, Eindhoven, The Netherlands
| | - A van de Stolpe
- Philips Research Laboratories, High Tech Campus 11, Eindhoven, The Netherlands
| | - R H A M Vossen
- Leiden Genome Technology Center (LGTC), Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - S Y Anvar
- Leiden Genome Technology Center (LGTC), Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - J A Foekens
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - S Sleijfer
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - J W M Martens
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Can Mitochondria DNA Provide a Novel Biomarker for Evaluating the Risk and Prognosis of Colorectal Cancer? DISEASE MARKERS 2017; 2017:5189803. [PMID: 28408773 PMCID: PMC5376434 DOI: 10.1155/2017/5189803] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 02/14/2017] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) was one of the most frequent cancers worldwide. Accurate risk and prognosis evaluation could obtain better quality of life and longer survival time for the patients. Current research hotspot was focus on the gene biomarker to evaluate the risk and prognosis. Mitochondrion contains its own DNA and regulates self-replicating so that it can be as a candidate biomarker for evaluating the risk and prognosis of colorectal cancer. But there were already huge controversies on this issue. The review was to summarize current viewpoints of the controversial issues and described our understanding from the four aspects including mtDNA copy number, mitochondrial displacement loop, mtDNA variation, and mtDNA microsatellite instability, wishing the summary of the mtDNA in colorectal cancer could provide a meaningful reference or a valuable direction in the future studies.
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Hosseini M, Kasraian Z, Rezvani HR. Energy metabolism in skin cancers: A therapeutic perspective. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2017; 1858:712-722. [PMID: 28161328 DOI: 10.1016/j.bbabio.2017.01.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/20/2017] [Accepted: 01/23/2017] [Indexed: 12/13/2022]
Abstract
Skin cancers are the most common cancers worldwide. The incidence of common skin cancers, including basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and melanomas, continues to rise by 5 to 7% per year, mainly due to ultraviolet (UV) exposure and partly because of aging. This suggests an urgent necessity to improve the level of prevention and protection for skin cancers as well as developing new prognostic and diagnostic markers of skin cancers. Moreover, despite innovative therapies especially in the fields of melanoma and carcinomas, new therapeutic options are needed to bypass resistance to targeted therapies or treatment's side effects. Since reprogramming of cellular metabolism is now considered as a hallmark of cancer, some of the recent findings on the role of energy metabolism in skin cancer initiation and progression as well as its effect on the response to targeted therapies are discussed in this review. This article is part of a Special Issue entitled Mitochondria in cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
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Affiliation(s)
- Mohsen Hosseini
- Inserm U 1035, 33076 Bordeaux, France; Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France
| | - Zeinab Kasraian
- Inserm U 1035, 33076 Bordeaux, France; Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France
| | - Hamid Reza Rezvani
- Inserm U 1035, 33076 Bordeaux, France; Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France; Centre de Référence pour les Maladies Rares de la Peau, CHU de Bordeaux, France.
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9
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Spotlight on the relevance of mtDNA in cancer. Clin Transl Oncol 2016; 19:409-418. [PMID: 27778302 DOI: 10.1007/s12094-016-1561-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 10/06/2016] [Indexed: 02/06/2023]
Abstract
The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer's biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA.
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Görlach A, Dimova EY, Petry A, Martínez-Ruiz A, Hernansanz-Agustín P, Rolo AP, Palmeira CM, Kietzmann T. Reactive oxygen species, nutrition, hypoxia and diseases: Problems solved? Redox Biol 2015; 6:372-385. [PMID: 26339717 PMCID: PMC4565025 DOI: 10.1016/j.redox.2015.08.016] [Citation(s) in RCA: 258] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 08/21/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Within the last twenty years the view on reactive oxygen species (ROS) has changed; they are no longer only considered to be harmful but also necessary for cellular communication and homeostasis in different organisms ranging from bacteria to mammals. In the latter, ROS were shown to modulate diverse physiological processes including the regulation of growth factor signaling, the hypoxic response, inflammation and the immune response. During the last 60–100 years the life style, at least in the Western world, has changed enormously. This became obvious with an increase in caloric intake, decreased energy expenditure as well as the appearance of alcoholism and smoking; These changes were shown to contribute to generation of ROS which are, at least in part, associated with the occurrence of several chronic diseases like adiposity, atherosclerosis, type II diabetes, and cancer. In this review we discuss aspects and problems on the role of intracellular ROS formation and nutrition with the link to diseases and their problematic therapeutical issues.
Oxidative stress is linked to overnutrition, obesity and associated diseases or cancer. Reactive oxygen species (ROS) are crucially involved in modulation of signaling cascades. NOX proteins and hypoxia contribute to formation of ROS under different nutrient regimes. ROS are powerful post-transcriptional and epigenetic regulators. Treatment of obesity with antioxidants requires more, larger, and better monitored clinical trials.
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Affiliation(s)
- Agnes Görlach
- Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Elitsa Y Dimova
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Andreas Petry
- Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Antonio Martínez-Ruiz
- Servicio de Immunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
| | - Pablo Hernansanz-Agustín
- Servicio de Immunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain; Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Anabela P Rolo
- Department of Life Sciences, University of Coimbra and Center for Neurosciences and Cell Biology, University of Coimbra, Portugal
| | - Carlos M Palmeira
- Department of Life Sciences, University of Coimbra and Center for Neurosciences and Cell Biology, University of Coimbra, Portugal
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
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11
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Mitochondrial DNA copy number in peripheral blood and melanoma risk. PLoS One 2015; 10:e0131649. [PMID: 26110424 PMCID: PMC4482392 DOI: 10.1371/journal.pone.0131649] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 06/05/2015] [Indexed: 02/07/2023] Open
Abstract
Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure).
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12
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Ganepola GAP, Nizin J, Rutledge JR, Chang DH. Use of blood-based biomarkers for early diagnosis and surveillance of colorectal cancer. World J Gastrointest Oncol 2014; 6:83-97. [PMID: 24734154 PMCID: PMC3981973 DOI: 10.4251/wjgo.v6.i4.83] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 03/08/2014] [Accepted: 03/17/2014] [Indexed: 02/05/2023] Open
Abstract
Early screening for colorectal cancer (CRC) holds the key to combat and control the increasing global burden of CRC morbidity and mortality. However, the current available screening modalities are severely inadequate because of their high cost and cumbersome preparatory procedures that ultimately lead to a low participation rate. People simply do not like to have colonoscopies. It would be ideal, therefore, to develop an alternative modality based on blood biomarkers as the first line screening test. This will allow for the differentiation of the general population from high risk individuals. Colonoscopy would then become the secondary test, to further screen the high risk segment of the population. This will encourage participation and therefore help to reach the goal of early detection and thereby reduce the anticipated increasing global CRC incidence rate. A blood-based screening test is an appealing alternative as it is non-invasive and poses minimal risk to patients. It is easy to perform, can be repeated at shorter intervals, and therefore would likely lead to a much higher participation rate. This review surveys various blood-based test strategies currently under investigation, discusses the potency of what is available, and assesses how new technology may contribute to future test design.
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13
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Samoylenko A, Hossain JA, Mennerich D, Kellokumpu S, Hiltunen JK, Kietzmann T. Nutritional countermeasures targeting reactive oxygen species in cancer: from mechanisms to biomarkers and clinical evidence. Antioxid Redox Signal 2013; 19:2157-96. [PMID: 23458328 PMCID: PMC3869543 DOI: 10.1089/ars.2012.4662] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 02/08/2013] [Accepted: 03/01/2013] [Indexed: 02/06/2023]
Abstract
Reactive oxygen species (ROS) exert various biological effects and contribute to signaling events during physiological and pathological processes. Enhanced levels of ROS are highly associated with different tumors, a Western lifestyle, and a nutritional regime. The supplementation of food with traditional antioxidants was shown to be protective against cancer in a number of studies both in vitro and in vivo. However, recent large-scale human trials in well-nourished populations did not confirm the beneficial role of antioxidants in cancer, whereas there is a well-established connection between longevity of several human populations and increased amount of antioxidants in their diets. Although our knowledge about ROS generators, ROS scavengers, and ROS signaling has improved, the knowledge about the direct link between nutrition, ROS levels, and cancer is limited. These limitations are partly due to lack of standardized reliable ROS measurement methods, easily usable biomarkers, knowledge of ROS action in cellular compartments, and individual genetic predispositions. The current review summarizes ROS formation due to nutrition with respect to macronutrients and antioxidant micronutrients in the context of cancer and discusses signaling mechanisms, used biomarkers, and its limitations along with large-scale human trials.
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Affiliation(s)
- Anatoly Samoylenko
- Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu, Finland
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Jubayer Al Hossain
- Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Daniela Mennerich
- Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Sakari Kellokumpu
- Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu, Finland
| | | | - Thomas Kietzmann
- Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu, Finland
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Dakubo GD. Mitochondrial genome analysis in biofluids for early cancer detection and monitoring. ACTA ACUST UNITED AC 2013; 2:263-75. [PMID: 23495657 DOI: 10.1517/17530059.2.3.263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Biofluids collected in a non-invasive fashion are potentially valuable samples for assaying genomic alterations for early detection and monitoring of cancer. The low cellularity and nucleic acid content in biofluids, the high copy number of the mitochondrial genome (mtgenome) and its noted early imprints in cancer make this molecule theoretically more sensitive than nuclear targets to measure for early cancer detection. OBJECTIVE This review explores mtgenome analysis in biofluids and addresses the question of whether targeting the mtgenome in biofluids is superior or equivalent to analysis of nuclear genomic alterations. METHODS The literature was retrieved from PubMed using a combination of the following keywords: mtDNA, mutation, deletion, content, copy number, cancer, biofluids, bodily fluids and the specific cancers described here. Studies that analyzed mtgenome alterations in biofluids were included. Analytical methods available for assaying mtgenome changes in biofluids are discussed. RESULTS Despite the limited data available, mtgenome changes in biofluids have been demonstrated in a wide variety of cancer patients. CONCLUSION Mtgenome analysis in biofluids is feasible and relatively easy. Despite the paucity of data, tumor-specific mtgenome changes are observed in biofluids of cancer patients. Given the multiple copies per cell of the mtgenome, future cancer detection efforts should consider complementary analysis of mtgenome changes in biofluids.
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Affiliation(s)
- Gabriel D Dakubo
- Senior Scientist Genesis Genomics, Inc., 290 Munro Street, Ste 1000, Thunder Bay, Ontario, P7A 7T1, Canada +1 807 768 4516 ; +1 807 346 8105 ;
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Parr RL, Jakupciak JP, Birch-Machin MA, Dakubo GD. The mitochondrial genome: a biosensor for early cancer detection? ACTA ACUST UNITED AC 2013; 1:169-82. [PMID: 23489304 DOI: 10.1517/17530059.1.2.169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Mutations in the mitochondrial genome have been reported as biomarkers for the detection of cancer. Hallmarks of cancer development include the accumulation of genetic alterations in the mitochondrial and nuclear genomes. Damage to mitochondria affects energy metabolism, generation of reactive oxygen species, apoptosis, cell growth and other processes that contribute to the neoplastic process. Furthermore, mitochondrial DNA mutations occur frequently in cancer. Little work has been done to link a pathway between mitochondrial mutations and cancer etiology. Volumes of work have been reported on the association of mitochondrial mutations and almost all types of cancer including the use of body fluids for early detection. This review examines the measurement of mitochondrial mutations for the application of detecting human tumor tissue.
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Affiliation(s)
- Ryan L Parr
- Vice President of Research, Genesis Genomics, Inc., 290 Munro Street, Ste 1000, Thunder Bay, Ontario, P7A 7T1, Canada +1 807 346 8100; +1 807 346 8105 ;
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Guo XG, Liu CT, Dai H, Guo QN. Mutations in the mitochondrial ATPase6 gene are frequent in human osteosarcoma. Exp Mol Pathol 2012; 94:285-8. [PMID: 22542792 DOI: 10.1016/j.yexmp.2012.04.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 02/12/2012] [Accepted: 04/10/2012] [Indexed: 11/25/2022]
Abstract
To explore the polymorphisms and mutations of mitochondrial ATPase6 gene in Chinese patients with osteosarcoma and their possible association with carcinogenesis, direct DNA sequencing method was used to detect the variants of the mitochondrial ATPase6 gene in 39 patients with osteosarcoma. We found mutations of the mitochondrial ATPase6 gene in 24/39 (61.5%) of the tested osteosarcoma samples, and identified 27 variant sites in ATPase6 coding regions. We did not detect any new polymorphisms in osteosarcoma, nor was there any association between variants and the three histopathological subtypes. These data demonstrated that mtDNA mutations within the ATPase6 gene are a frequent event in Chinese patients with osteosarcoma.
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Affiliation(s)
- Xue-Guang Guo
- Respiratory Department of Nanlou, Chinese People's Liberation Army General Hospital, 28# Fuxing Road, Haidian District, Beijing 100853, China
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Abstract
Mitochondria are ubiquitous organelles in eukaryotic cells principally responsible for regulating cellular energy metabolism, free radical production, and the execution of apoptotic pathways. Abnormal oxidative phosphorylation (OXPHOS) and aerobic metabolism as a result of mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. In the past decades, numerous somatic mutations in both the coding and control regions of mitochondrial DNA (mtDNA) have been extensively examined in a broad range of primary human cancers, underscoring that accumulation of mtDNA alterations may be a critical factor in eliciting persistent mitochondrial defects and consequently contributing to cancer initiation and progression. However, the roles of these mtDNA mutations in the carcinogenic process remain largely unknown. This review outlines a wide variety of somatic mtDNA mutations identified in common human malignancies and highlights recent advances in understanding the causal roles of mtDNA variations in neoplastic transformation and tumor progression. In addition, it briefly illustrates how mtDNA alterations activate mitochondria-to-nucleus retrograde signaling so as to modulate the expression of relevant nuclear genes or induce epigenetic changes and promote malignant phenotypes in cancer cells. The present state of our knowledge regarding how mutational changes in the mitochondrial genome could be used as a diagnostic biomarker for early detection of cancer and as a potential target in the development of new therapeutic approaches is also discussed. These findings strongly indicate that mtDNA mutations exert a crucial role in the pathogenic mechanisms of tumor development, but continued investigations are definitely required to further elucidate the functional significance of specific mtDNA mutations in the etiology of human cancers.
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Kasiviswanathan R, Gustafson MA, Copeland WC, Meyer JN. Human mitochondrial DNA polymerase γ exhibits potential for bypass and mutagenesis at UV-induced cyclobutane thymine dimers. J Biol Chem 2011; 287:9222-9. [PMID: 22194617 DOI: 10.1074/jbc.m111.306852] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Cyclobutane thymine dimers (T-T) comprise the majority of DNA damage caused by short wavelength ultraviolet radiation. These lesions generally block replicative DNA polymerases and are repaired by nucleotide excision repair or bypassed by translesion polymerases in the nucleus. Mitochondria lack nucleotide excision repair, and therefore, it is important to understand how the sole mitochondrial DNA polymerase, pol γ, interacts with irreparable lesions such as T-T. We performed in vitro DNA polymerization assays to measure the kinetics of incorporation opposite the lesion and bypass of the lesion by pol γ with a dimer-containing template. Exonuclease-deficient pol γ bypassed thymine dimers with low relative efficiency; bypass was attenuated but still detectable when using exonuclease-proficient pol γ. When bypass did occur, pol γ misincorporated a guanine residue opposite the 3'-thymine of the dimer only 4-fold less efficiently than it incorporated an adenine. Surprisingly, the pol γ exonuclease-proficient enzyme excised the incorrectly incorporated guanine at similar rates irrespective of the nature of the thymines in the template. In the presence of all four dNTPs, pol γ extended the primer after incorporation of two adenines opposite the lesion with relatively higher efficiency compared with extension past either an adenine or a guanine incorporated opposite the 3'-thymine of the T-T. Our results suggest that T-T usually stalls mitochondrial DNA replication but also suggest a mechanism for the introduction of point mutations and deletions in the mitochondrial genomes of chronically UV-exposed cells.
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Affiliation(s)
- Rajesh Kasiviswanathan
- Laboratory of Molecular Genetics, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
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19
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Ebner S, Lang R, Mueller EE, Eder W, Oeller M, Moser A, Koller J, Paulweber B, Mayr JA, Sperl W, Kofler B. Mitochondrial haplogroups, control region polymorphisms and malignant melanoma: a study in middle European Caucasians. PLoS One 2011; 6:e27192. [PMID: 22174736 PMCID: PMC3235102 DOI: 10.1371/journal.pone.0027192] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 10/11/2011] [Indexed: 11/18/2022] Open
Abstract
Background Because mitochondria play an essential role in energy metabolism, generation of reactive oxygen species (ROS), and apoptosis, sequence variation in the mitochondrial genome has been postulated to be a contributing factor to the etiology of multifactorial age-related diseases, including cancer. The aim of the present study was to compare the frequencies of mitochondrial DNA (mtDNA) haplogroups as well as control region (CR) polymorphisms of patients with malignant melanoma (n = 351) versus those of healthy controls (n = 1598) in Middle Europe. Methodology and Principal Findings Using primer extension analysis and DNA sequencing, we identified all nine major European mitochondrial haplogroups and known CR polymorphisms. The frequencies of the major mitochondrial haplogroups did not differ significantly between patients and control subjects, whereas the frequencies of the one another linked CR polymorphisms A16183C, T16189C, C16192T, C16270T and T195C were significantly higher in patients with melanoma compared to the controls. Regarding clinical characteristics of the patient cohort, none of the nine major European haplogroups was associated with either Breslow thickness or distant metastasis. The CR polymorphisms A302CC-insertion and T310C-insertion were significantly associated with mean Breslow thickness, whereas the CR polymorphism T16519C was associated with metastasis. Conclusions and Significance Our results suggest that mtDNA variations could be involved in melanoma etiology and pathogenesis, although the functional consequence of CR polymorphisms remains to be elucidated.
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Affiliation(s)
- Sabine Ebner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Roland Lang
- Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Edith E. Mueller
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Waltraud Eder
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Michaela Oeller
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Moser
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Josef Koller
- Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Bernhard Paulweber
- Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Johannes A. Mayr
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Wolfgang Sperl
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
- * E-mail:
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Kulawiec M, Salk JJ, Ericson NG, Wanagat J, Bielas JH. Generation, function, and prognostic utility of somatic mitochondrial DNA mutations in cancer. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2010; 51:427-439. [PMID: 20544883 DOI: 10.1002/em.20582] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Exciting new studies are increasingly strengthening the link between mitochondrial mutagenesis and tumor progression. Here we provide a comprehensive review and meta-analysis of studies reporting on mitochondrial DNA mutations in common human cancers. We discuss possible mechanisms by which mitochondrial DNA mutations may influence carcinogenesis, outline important caveats for interpreting the detected mutations--particularly differentiating causality from association--and suggest how new mutational assays may help resolve fundamental controversies in the field and delineate the origin and expansion of neoplastic cell lineages. Finally, we discuss the potential clinical utility of mtDNA mutations for improving the sensitivity of early cancer diagnosis, rapidly detecting cancer recurrence, and predicting the disease outcome.
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Affiliation(s)
- Mariola Kulawiec
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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22
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Birch-Machin MA, Swalwell H. How mitochondria record the effects of UV exposure and oxidative stress using human skin as a model tissue. Mutagenesis 2009; 25:101-7. [DOI: 10.1093/mutage/gep061] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
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Circulating tumor cells in gastrointestinal cancer. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2009; 17:577-82. [PMID: 19812887 DOI: 10.1007/s00534-009-0193-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2009] [Accepted: 09/01/2009] [Indexed: 12/11/2022]
Abstract
Since the first report in the nineteenth century, there have been numerous reports on the isolation and characterization of circulating tumor cells (CTCs) in peripheral blood in patients with various carcinomas. In general, CTCs have been observed in the peripheral blood of cancer patients at very low concentrations of 10(-7)-10(-8) of normal peripheral blood cells. The characterization is of considerable biomedical interest in order to understand how these cells can travel via the blood stream to anatomically distant sites and form metastatic disease. Recent progress in molecular oncology enables us to detect the CTCs in blood with highly sensitivity and specificity, and several studies have indicated the prognostic value of CTC detection in patients with gastrointestinal cancers. Detection and measurement of CTCs in patients with gastrointestinal cancers such as colorectal, gastric, and pancreatic cancers can be useful as a promising tool for judging tumor stage, predicting the distant metastasis and patient survival, and monitoring the response to cancer therapy. Standard procedures for CTC detection have to be established, and the clinical relevance should be verified in large-scale clinical trials. However, CTC detection is suggested to provide useful information for the tumor staging and anticancer treatments in clinical practices in the near future.
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24
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Xia P, Radpour R, Zachariah R, Fan AXC, Kohler C, Hahn S, Holzgreve W, Zhong XY. Simultaneous quantitative assessment of circulating cell-free mitochondrial and nuclear DNA by multiplex real-time PCR. Genet Mol Biol 2009; 32:20-4. [PMID: 21637641 PMCID: PMC3032948 DOI: 10.1590/s1415-47572009000100003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Accepted: 07/24/2008] [Indexed: 12/03/2022] Open
Abstract
Quantification of circulating nucleic acids in plasma and serum could be used as a non-invasive diagnostic tool for monitoring a wide variety of diseases and conditions. We describe here a rapid, simple and accurate multiplex real-time PCR method for direct synchronized analysis of circulating cell-free (ccf) mitochondrial (mtDNA) and nuclear (nDNA) DNA in plasma and serum samples. The method is based on one-step multiplex real-time PCR using a FAM-labeled MGB probe and primers to amplify the mtDNA sequence of the ATP 8 gene, and a VIC-labeled MGB probe and primers to amplify the nDNA sequence of the glycerinaldehyde-3-phosphate-dehydrogenase (GAPDH) gene, in plasma and serum samples simultaneously. The efficiencies of the multiplex assays were measured in serial dilutions. Based on the simulation of the PCR reaction kinetics, the relative quantities of ccf mtDNA were calculated using a very simple equation. Using our optimised real-time PCR conditions, close to 100% efficiency was obtained from the two assays. The two assays performed in the dilution series showed very good and reproducible correlation to each other. This optimised multiplex real-time PCR protocol can be widely used for synchronized quantification of mtDNA and nDNA in different samples, with a very high rate of efficiency.
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Affiliation(s)
- Peng Xia
- Laboratory for Prenatal Medicine and Gynaecological Oncology, Women's Hospital, University of Basel Switzerland
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25
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Losanoff JE, Zhu W, Qin W, Mannello F, Sauter ER. Can mitochondrial DNA mutations in circulating white blood cells and serum be used to detect breast cancer? Breast 2008; 17:540-542. [PMID: 18571924 DOI: 10.1016/j.breast.2008.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2008] [Revised: 04/25/2008] [Accepted: 04/28/2008] [Indexed: 01/23/2023] Open
Abstract
Circulating mitochondrial DNA (mtDNA) affected by mutations have been detected in melanoma, prostate cancer, and digestive neoplasms involving the pancreas, liver, and the colon. We sought to detect such mutations in women with breast cancer to assess if the method could be used to aid in the diagnosis of breast cancer. Blood was collected and mtDNA extracted; 27 samples included 14 patients who had breast cancer and 13 healthy controls. White blood cells and serum were separated. The mitochondrial D-loop region was amplified using PCR followed by automated DNA sequencing. The collected data was analyzed with computer software to detect both polymorphisms and mutations. mtDNA sequencing was successful in 93% of the samples (n=23). No mutations were found in any of the study groups. Polymorphisms were detected in all specimens, three of which had not been previously reported. The method used did not detect mtDNA mutations in the blood of women with breast cancer, but was extremely sensitive in polymorphism detection.
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Affiliation(s)
- Julian E Losanoff
- Department of Surgery, John D Dingell VAMC and Wayne State University, Detroit, MI, USA
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26
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Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta Rev Cancer 2006; 1775:181-232. [PMID: 17137717 DOI: 10.1016/j.bbcan.2006.10.001] [Citation(s) in RCA: 422] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2006] [Revised: 10/04/2006] [Accepted: 10/04/2006] [Indexed: 12/23/2022]
Abstract
It has been known for decades that it is possible to detect small amounts of extracellular nucleic acids in plasma and serum of healthy and diseased human beings. The unequivocal proof that part of these circulating nucleic acids (CNAs) is of tumor origin, initiated a surge of studies which confirmed and extended the original observations. In the past few years many experiments showed that tumor-associated alterations can be detected at the DNA and RNA level. At the DNA level the detection of point mutations, microsatellite alterations, chromosomal alterations, i.e. inversion and deletion, and hypermethylation of promoter sequences were demonstrated. At the RNA level the overexpression of tumor-associated genes was shown. These observations laid the foundation for the development of assays for an early detection of cancer as well as for other clinical means.
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Affiliation(s)
- M Fleischhacker
- Charité, Universitätsmedizin Berlin, Medizinische Klinik mS Onkologie u Hämatologie, CCM, Charitéplatz 1, 10117 Berlin, Germany.
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Abstract
Mitochondria can perform multiple cellular functions including energy production, cell proliferation and apoptosis. These organelles contain their own genetic material, mitochondrial DNA (mtDNA), which is maternally inherited. Although much smaller than the nuclear genome, mtDNA is equally important, as it has been hypothesized to play a crucial role in ageing and carcinogenesis. This is partly due to the fact that mitochondria represent the major site for the generation of cellular oxidative stress and play a key role in mediating programmed cell death (apoptosis). Damage to mtDNA is therefore an important contributor to human ageing, cancer and neurodegenerative diseases. The most relevant footprints of mtDNA damage are point mutations of single bases, or deletions of the 16.5-kb mitochondrial genome. This review will focus on the key roles of mitochondrial function and mtDNA in oxidative stress production and as a mediator of apoptosis, and on the use of mtDNA as a biomarker of sun exposure. This will be related to the contribution of mitochondria and mtDNA in the ageing process and cancer, with a specific focus on human skin. In conclusion, it is likely that the interplay between nuclear and mitochondrial genes may hold the final understanding of the mitochondrial role in these disease processes.
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Affiliation(s)
- M A Birch-Machin
- Dermatological Sciences, School of Clinical and Laboratory Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
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28
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Parr RL, Dakubo GD, Thayer RE, McKenney K, Birch-Machin MA. Mitochondrial DNA as a potential tool for early cancer detection. Hum Genomics 2006; 2:252-7. [PMID: 16460650 PMCID: PMC3500203 DOI: 10.1186/1479-7364-2-4-252] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The recent surge in mitochondrial research has been driven by the identification of mitochondria-associated diseases and the role of mitochondria in apoptosis. Both of these aspects have identified mitochondrial analysis as a vital component of medical research. Moreover, mitochondria have been implicated in the process of carcinogenesis because of their vital role in energy production, nuclear-cytoplasmic signal integration and control of metabolic pathways. Interestingly, at some point during neoplastic transformation, there is an increase in reactive oxygen species, which damage the mitochondrial genome. This accelerates the somatic mutation rate of mitochondrial DNA. It has been proposed that these mutations may serve as an early indication of potential cancer development and may represent a means for tracking tumour progression. The purpose of this review is to explore the potential utility that these mutations may afford for the identification and monitoring of neoplasia and malignant transformation where appropriate body fluids or non-invasive tissue access is available for mitochondrial DNA recovery. Specifically, prostate, breast, colorectal, skin and lung cancers are discussed.
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Affiliation(s)
- Ryan L Parr
- Genesis Genomics Inc, Thunder Bay, Ontario, P7B 5Z5, Canada.
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29
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Abstract
Many models of tumour formation have been put forth so far. In general they involve mutations in at least three elements within the cell: oncogenes, tumour suppressors and regulators of telomere replication. Recently numerous mutations in mitochondria have been found in many tumours, whereas they were absent in normal tissues from the same individual. The presence of mutations, of course, does not prove that they play a causative role in development of neoplastic lesions and progression; however, the key role played by mitochondria in both apoptosis and generation of DNA-damaging reactive oxygen species might indicate that the observed mutations contribute to tumour development. Recent experiments with nude mice have proven that mtDNA mutations are indeed responsible for tumour growth and exacerbated ROS production. This review describes mtDNA mutations in main types of human neoplasia.
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Affiliation(s)
- Anna M Czarnecka
- Department of Genetics, University of Warsaw, ul. Pawinskiego 5a, 02-106 Warszawa, Poland
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Mori T, O'Day SJ, Umetani N, Martinez SR, Kitago M, Koyanagi K, Kuo C, Takeshima TL, Milford R, Wang HJ, Vu VD, Nguyen SL, Hoon DSB. Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. J Clin Oncol 2005; 23:9351-9358. [PMID: 16361635 PMCID: PMC2856438 DOI: 10.1200/jco.2005.02.9876] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Currently, no validated blood-based assays accurately predict treatment response or outcome in melanoma patients. We hypothesized that methylation of tumor-related genes detected in serum DNA could predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy (BC) for metastatic melanoma. PATIENTS AND METHODS American Joint Committee on Cancer stage IV melanoma patients (N = 50) had blood drawn before administration of BC. Patients (n = 47) were classified as BC responders or nonresponders. Responders (n = 23) demonstrated a complete or partial response following BC; nonresponders (n = 24) demonstrated progressive disease. Hypermethylation of Ras association domain family 1 (RASSF1A), retinoic acid receptor-beta2 (RAR-beta2), and O6-methylguanine DNA methyltransferase (MGMT) genes were assessed by methylation-specific polymerase chain reaction. RESULTS Circulating methylated RASSF1A was significantly less frequent for responders (three of 23 patients; 13%) than nonresponders (10 of 24 patients; 42%; P = .028). Patients with RASSF1A, RAR-beta2, or at least one serum methylated gene had significantly worse overall survival than patients with no methylated genes (log-rank, P = .013, .021, and .01, respectively). Methylated RASSF1A was the only factor that significantly correlated with overall survival and BC response (risk ratio, 2.38; 95% CI, 1.16 to 4.86; P = .018; odds ratio = 0.21; 95% CI, 0.05 to 0.90; P = .036). CONCLUSION Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.
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Affiliation(s)
- Takuji Mori
- Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA
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