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Dias BDS, Antunes SR, Pinheiro DDR, Burbano RMR, Borges BDN. Mitochondrial Complex I Molecular Alterations in Sapajus apella as a Human Gastric Carcinogenesis Model After MNU Exposure. J Med Primatol 2025; 54:e70017. [PMID: 40166901 PMCID: PMC11959525 DOI: 10.1111/jmp.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 03/13/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025]
Abstract
INTRODUCTION Gastric cancer (GC) remains among the top five global health problems. Therefore, comprehending the tumor energetic behavior is critical to understanding its progression. This study aimed to investigate mitochondrial DNA (mtDNA) alterations in GC cancer cell lines in an animal model. MATERIAL AND METHODS Four mitochondrial genes (COI, ATP8, ND1, and ND3) were analyzed in GC (AGP01, ACP02, ACP03, and PG100) and control (Walker 256 carcinosarcoma) cell lines inoculated in Sapajus apella, exposed and not exposed to N-methyl-N-nitrosourea. RESULTS Two synonymous alterations were identified in ND1. In ND3, a non-synonymous alteration (A10398G ➔ Thr114Ala) may decrease the respiratory chain Complex I efficiency, enhancing cellular reactive oxygen species and contributing to mtDNA damage. As alterations in ND1 and ND3 were observed in highly aggressive cell lines, our results suggest these genes may play crucial roles in energetic efficiency and gastric carcinogenesis.
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Affiliation(s)
- Bárbara dos Santos Dias
- Albert Einstein Research and Educational InstituteHospital Israelita Albert EinsteinSão PauloSão Paulo estadoBrazil
| | | | | | - Rommel Mario Rodriguez Burbano
- Molecular Biology LaboratoryOphir Loyola HospitalBelémParáBrazil
- Cellular Biology Laboratory, Institute of Biological SciencesFederal University of ParáBelémParáBrazil
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Kabelikova P, Ivovic D, Sumbalova Z, Karhanek M, Tatayova L, Skopkova M, Cagalinec M, Bruderova V, Roska J, Jurkovicova D. Mitochondrial genome variability and metabolic alterations reveal new biomarkers of resistance in testicular germ cell tumors. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:54. [PMID: 39802950 PMCID: PMC11724352 DOI: 10.20517/cdr.2024.141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/11/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025]
Abstract
Aim: Mutations in the mitochondrial (mt) genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells. This study explores the mutational status of the mt genome of cisplatin-resistant vs. -sensitive testicular germ cell tumor (TGCT) cells and explores its association with their respiration parameters, expression of respiratory genes, and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs. Methods: Using Illumina sequencing with Twist Enrichment Panel, the mutations of mt genomes of sensitive 2102EP, H12.1, NTERA-2, T-cam and resistant 2102EP Cis, H12.1 ODM, 1411HP, 1777NRpmet, NTERA-2 Cis and T-cam Cis cell lines were identified. The mt respiration of the cells was assessed using high-resolution respirometry method (O2k-respirometer Oroboros) and the differential expression profiles of mt respiratory genes were determined using RT-qPCR. Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay. Results: In resistant TGCT cells, new mutations in mt genes MT-ND1-6, MT-RNR, MT-CO1-3, MT-ATP6, and MT-CYB were recognized. The respiratory rates of the 1777NRpmet cell line were the highest, while those of the 1411HP line the lowest; rates of the control and all other TGCT cell lines fell between these two lines. The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines. Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation (OXPHOS), while glycolysis was typical for resistant NTERA-2 Cis, 2102EP Cis and 1411HP cell lines. Metastatic 1777NRpmet cells seem to utilize both. An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence, sensitive H12.1 preferring glycolysis, while resistant H12.1ODM OXPHOS. Conclusion: In summary, our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters, gene expression patterns and preferences for metabolic pathways, providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.
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Affiliation(s)
- Pavlina Kabelikova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Danica Ivovic
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Zuzana Sumbalova
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University in Bratislava, Bratislava 81108, Slovak Republic
| | - Miloslav Karhanek
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Lucia Tatayova
- Department of Medical Genetics, Medirex Inc., Bratislava 82104, Slovak Republic
| | - Martina Skopkova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Michal Cagalinec
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Vladimira Bruderova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Jan Roska
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
- Co-senior authors
| | - Dana Jurkovicova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
- Co-senior authors
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Nie Q, Zhang W, Lin S, Huang M, Li Y, Qiu Y, Li J, Chen X, Wang Y, Tong X, Wu J, He P, Cai Q, Chen L, Chen M, Guo W, Lin Y, Yu L, Hou J, Cai W, Chen H, Wang C, Fu F. Identification of sequence polymorphism in the D-loop region of mitochondrial DNA as a risk factor for breast cancer. Cancer Sci 2024; 115:4064-4073. [PMID: 39401980 PMCID: PMC11611757 DOI: 10.1111/cas.16353] [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: 04/01/2024] [Revised: 08/23/2024] [Accepted: 09/08/2024] [Indexed: 12/06/2024] Open
Abstract
Mitochondrial DNA (mtDNA) variations affect the efficiency of the electron transport chain and production of reactive oxygen species, contributing to carcinogenesis. The D-loop region of mtDNA has emerged as a variation hotspot region in human neoplasia; however, the potential contribution of these variations in breast cancer risk prediction remains unknown. We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in the entire D-loop region and breast cancer risk in Chinese women. Peripheral blood-isolated mtDNA from 2329 patients with breast cancer and 2328 cancer-free controls was examined for SNPs. In the combined cohort, we used traditional risk factors, susceptibility germline polymorphisms, and logistic regression analysis to evaluate the predictive value of susceptibility variants for breast cancer risk. We calculated the area under the receiver operating characteristic curve (AUC) as a measure. We also measured the content of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Individual polymorphisms SNP573 were significantly associated with breast cancer risk in both the discovery and validation cohorts. In the combined cohort, the AUC of the traditional risk factors was 64.3%; after adding susceptibility variants, the AUC was 64.9% (DeLong test, p = 0.007). 8-OHdG levels were significantly higher in patients with breast cancer than in controls and higher in individuals with SNP573 than in those negative for this variation. Overall, oxidative stress might be associated with the risk of breast cancer, and SNP573 might be associated with oxidative stress. Our results indicate the risk potential of polymorphisms in the D-loop region in breast cancer in Southern China.
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Shelton SD, House S, Martins Nascentes Melo L, Ramesh V, Chen Z, Wei T, Wang X, Llamas CB, Venigalla SSK, Menezes CJ, Allies G, Krystkiewicz J, Rösler J, Meckelmann SW, Zhao P, Rambow F, Schadendorf D, Zhao Z, Gill JG, DeBerardinis RJ, Morrison SJ, Tasdogan A, Mishra P. Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis. SCIENCE ADVANCES 2024; 10:eadk8801. [PMID: 39485847 PMCID: PMC11529715 DOI: 10.1126/sciadv.adk8801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 09/27/2024] [Indexed: 11/03/2024]
Abstract
Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.
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Affiliation(s)
- Spencer D. Shelton
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sara House
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Luiza Martins Nascentes Melo
- Department of Dermatology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site, Essen, Germany
| | - Vijayashree Ramesh
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhenkang Chen
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tao Wei
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xun Wang
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Claire B. Llamas
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Siva Sai Krishna Venigalla
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Cameron J. Menezes
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gabriele Allies
- Department of Dermatology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site, Essen, Germany
| | - Jonathan Krystkiewicz
- Department of Dermatology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site, Essen, Germany
| | - Jonas Rösler
- Department of Dermatology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site, Essen, Germany
- Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany
| | - Sven W. Meckelmann
- Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany
| | - Peihua Zhao
- Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Florian Rambow
- Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site, Essen, Germany
- National Center for Tumor Diseases (NCT)-West, Campus Essen, and Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
| | - Zhiyu Zhao
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jennifer G. Gill
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sean J. Morrison
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Alpaslan Tasdogan
- Department of Dermatology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site, Essen, Germany
| | - Prashant Mishra
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Cabané P, Correa C, Bode I, Aguilar R, Elorza AA. Biomarkers in Thyroid Cancer: Emerging Opportunities from Non-Coding RNAs and Mitochondrial Space. Int J Mol Sci 2024; 25:6719. [PMID: 38928426 PMCID: PMC11204084 DOI: 10.3390/ijms25126719] [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: 04/20/2024] [Revised: 06/01/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Thyroid cancer diagnosis primarily relies on imaging techniques and cytological analyses. In cases where the diagnosis is uncertain, the quantification of molecular markers has been incorporated after cytological examination. This approach helps physicians to make surgical decisions, estimate cancer aggressiveness, and monitor the response to treatments. Despite the availability of commercial molecular tests, their widespread use has been hindered in our experience due to cost constraints and variability between them. Thus, numerous groups are currently evaluating new molecular markers that ultimately will lead to improved diagnostic certainty, as well as better classification of prognosis and recurrence. In this review, we start reviewing the current preoperative testing methodologies, followed by a comprehensive review of emerging molecular markers. We focus on micro RNAs, long non-coding RNAs, and mitochondrial (mt) signatures, including mtDNA genes and circulating cell-free mtDNA. We envision that a robust set of molecular markers will complement the national and international clinical guides for proper assessment of the disease.
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Affiliation(s)
- Patricio Cabané
- Department of Head and Neck Surgery, Clinica INDISA, Santiago 7520440, Chile; (P.C.); (C.C.)
- Faculty of Medicine, Universidad Andres Bello, Santiago 8370071, Chile
- Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
| | - Claudio Correa
- Department of Head and Neck Surgery, Clinica INDISA, Santiago 7520440, Chile; (P.C.); (C.C.)
- Faculty of Medicine, Universidad Andres Bello, Santiago 8370071, Chile
| | - Ignacio Bode
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370071, Chile;
| | - Rodrigo Aguilar
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370071, Chile;
| | - Alvaro A. Elorza
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370071, Chile;
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Hernandez-Prera JC. Molecular Pathology of Thyroid Tumors: Old Problems and New Concepts. Clin Lab Med 2024; 44:305-324. [PMID: 38821646 DOI: 10.1016/j.cll.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
The molecular signatures of many thyroid tumors have been uncovered. These discoveries have translated into clinical practice and are changing diagnostic and tumor classification paradigms. Here, the findings of recent studies are presented with special emphasis on how molecular insights are impacting the understating of RAS mutant thyroid nodules, Hürthel cell neoplasms, and unusual thyroid tumors, such as hyalinizing trabecular tumor, secretory carcinoma of the thyroid, and sclerosing mucoepidermoid carcinoma with eosinophilia. In addition, the utility of detecting actionable molecular alterations by immunohistochemistry in advanced and aggressive thyroid cancer is also discussed.
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Affiliation(s)
- Juan C Hernandez-Prera
- Department of Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
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Gezer E, Özer C, Şimşek T, Yaprak Bayrak B, Turan G, Çetinarslan B, Selek A, Cantürk Z, Sözen M, Köksalan D. N-Nitrosomorpholine-induced oncocytic transformation in rat endocrine organs. Eur J Med Res 2024; 29:64. [PMID: 38245764 PMCID: PMC10799477 DOI: 10.1186/s40001-024-01654-5] [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: 06/17/2023] [Accepted: 01/10/2024] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our study, we aimed to investigate the potential transformation of oncocytic cells in 6 endocrine organs, i.e., thyroid, adrenal and pituitary glands, pancreas, testis, and bone, of NMO-exposed rats. METHODS Thirty male rats were born and raised. Fifteen of them were given a single dose of 320 mg NMO per kg body weight, dissolved in drinking water, by a gavage tube. At the end of 52 weeks, the animals in both series were killed. Right after the killing, 6 different endocrine organs (hypophysis, thyroid, pancreas, adrenal gland, bone [femur], and testicles) of each animal were excised. RESULTS There was no evidence of oncocytic cell development in the control group. In contrast, oncocytes were observed in 8 out of 13 NMO-treated rats: 2 in the adrenal sections, 1 in the thyroid sections, 3 in the pituitary sections, and 2 in the pancreas sections. Thesticle and bone sections were completely normal. CONCLUSIONS We showed that NMO induced an oncocytic change in pancreas, thyroid, pituitary, and adrenal glands. To date, no identified specific environmental risk factors that lead to an oncocytic transformation in endocrine glands have been reported previously. Given the increasing prevalence of endocrine-disrupting chemicals in the environment, personal care products, manufactured goods, and food sources, there is a need to advance our understanding of the pathological mechanisms underlying oncocytosis in endocrine organs.
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Affiliation(s)
- Emre Gezer
- Division of Endocrinology and Metabolism, Darica Farabi Training and Research Hospital, Kocaeli, Turkey.
| | - Cüneyt Özer
- Experimental Medicine Research and Application Unit, Kocaeli University, Kocaeli, Turkey
| | - Turgay Şimşek
- Department of General Surgery, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Büşra Yaprak Bayrak
- Department of Pathology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Gupse Turan
- Department of Pathology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Berrin Çetinarslan
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Alev Selek
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Zeynep Cantürk
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Mehmet Sözen
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Damla Köksalan
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
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Abstract
Background: Very little was known about the molecular pathogenesis of thyroid cancer until the late 1980s. As part of the Centennial celebration of the American Thyroid Association, we review the historical discoveries that contributed to our current understanding of the genetic underpinnings of thyroid cancer. Summary: The pace of discovery was heavily dependent on scientific breakthroughs in nucleic acid sequencing technology, cancer biology, thyroid development, thyroid cell signaling, and growth regulation. Accordingly, we attempt to link the primary observations on thyroid cancer molecular genetics with the methodological and scientific advances that made them possible. Conclusions: The major genetic drivers of the common forms of thyroid cancer are now quite well established and contribute to a significant extent to how we diagnose and treat the disease. However, many challenges remain. Future work will need to unravel the complexity of thyroid cancer ecosystems, which is likely to be a major determinant of their biological behavior and on how they respond to therapy.
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Affiliation(s)
- James A. Fagin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Yuri E. Nikiforov
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Xu YC, Su J, Zhou JJ, Yuan Q, Han JS. Roles of MT-ND1 in Cancer. Curr Med Sci 2023; 43:869-878. [PMID: 37642864 DOI: 10.1007/s11596-023-2771-0] [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: 12/29/2022] [Accepted: 06/12/2023] [Indexed: 08/31/2023]
Abstract
The energy shift toward glycolysis is one of the hallmarks of cancer. Complex I is a vital enzyme complex necessary for oxidative phosphorylation. The mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1 (MT-ND1) is the largest subunit coded by mitochondria of complex I. The present study summarizes the structure and biological function of MT-ND1. From databases and literature, the expressions and mutations of MT-ND1 in a variety of cancers have been reviewed. MT-ND1 may be a biomarker for cancer diagnosis and prognosis. It is also a potential target for cancer therapy.
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Affiliation(s)
- Yi-Chun Xu
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China.
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, 201203, China.
| | - Jun Su
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, 201203, China
| | - Jia-Jing Zhou
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China
| | - Qing Yuan
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China
| | - Jun-Song Han
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China.
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, 201203, China.
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Shelton SD, House S, Ramesh V, Chen Z, Wei T, Wang X, Llamas CB, Venigalla SSK, Menezes CJ, Zhao Z, Gill JG, DeBerardinis RJ, Morrison SJ, Tasdogan A, Mishra P. Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.01.555986. [PMID: 37732192 PMCID: PMC10508716 DOI: 10.1101/2023.09.01.555986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.
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Affiliation(s)
- Spencer D. Shelton
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Sara House
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Vijayashree Ramesh
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Zhenkang Chen
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Tao Wei
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Xun Wang
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Claire B. Llamas
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Siva Sai Krishna Venigalla
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Cameron J. Menezes
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Zhiyu Zhao
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
| | - Jennifer G. Gill
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Sean J. Morrison
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Alpaslan Tasdogan
- Department of Dermatology, University Hospital Essen & German Cancer Consortium, Partner Site, Essen, Germany
| | - Prashant Mishra
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390 USA
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
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Gopal RK, Vantaku VR, Panda A, Reimer B, Rath S, To TL, Fisch AS, Cetinbas M, Livneh M, Calcaterra MJ, Gigliotti BJ, Pierce KA, Clish CB, Dias-Santagata D, Sadow PM, Wirth LJ, Daniels GH, Sadreyev RI, Calvo SE, Parangi S, Mootha VK. Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma. Cancer Discov 2023; 13:1904-1921. [PMID: 37262067 PMCID: PMC10401073 DOI: 10.1158/2159-8290.cd-22-0976] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 04/05/2023] [Accepted: 05/30/2023] [Indexed: 06/03/2023]
Abstract
Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. SIGNIFICANCE HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR-Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749.
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Affiliation(s)
- Raj K. Gopal
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Venkata R. Vantaku
- Harvard Medical School, Boston, Massachusetts
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Apekshya Panda
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Bryn Reimer
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Sneha Rath
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Tsz-Leung To
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Adam S. Fisch
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Murat Cetinbas
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Maia Livneh
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | | | | | - Kerry A. Pierce
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Clary B. Clish
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Dora Dias-Santagata
- Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Peter M. Sadow
- Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Lori J. Wirth
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Gilbert H. Daniels
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Thyroid Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Ruslan I. Sadreyev
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Sarah E. Calvo
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Sareh Parangi
- Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Vamsi K. Mootha
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
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12
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Bassal MA. The Interplay between Dysregulated Metabolism and Epigenetics in Cancer. Biomolecules 2023; 13:944. [PMID: 37371524 DOI: 10.3390/biom13060944] [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: 04/24/2023] [Revised: 05/21/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable of influencing, if not driving, epigenetic reprogramming. Conversely, epigenetic changes can drive altered and compensatory metabolic states. Cancer cells meticulously modify and control each of these two linked cellular processes in order to maintain their tumorigenic potential and capacity. This review aims to explore the interplay between these two processes and discuss how each affects the other, driving and enhancing tumorigenic states in certain contexts.
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Affiliation(s)
- Mahmoud Adel Bassal
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
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13
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Bernal-Tirapo J, Bayo Jiménez MT, Yuste-García P, Cordova I, Peñas A, García-Borda FJ, Quintela C, Prieto I, Sánchez-Ramos C, Ferrero-Herrero E, Monsalve M. Evaluation of Mitochondrial Function in Blood Samples Shows Distinct Patterns in Subjects with Thyroid Carcinoma from Those with Hyperplasia. Int J Mol Sci 2023; 24:ijms24076453. [PMID: 37047426 PMCID: PMC10094811 DOI: 10.3390/ijms24076453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/21/2023] [Accepted: 03/25/2023] [Indexed: 04/03/2023] Open
Abstract
Metabolic adaptations are a hallmark of cancer and may be exploited to develop novel diagnostic and therapeutic tools. Only about 50% of the patients who undergo thyroidectomy due to suspicion of thyroid cancer actually have the disease, highlighting the diagnostic limitations of current tools. We explored the possibility of using non-invasive blood tests to accurately diagnose thyroid cancer. We analyzed blood and thyroid tissue samples from two independent cohorts of patients undergoing thyroidectomy at the Hospital Universitario 12 de Octubre (Madrid, Spain). As expected, histological comparisons of thyroid cancer and hyperplasia revealed higher proliferation and apoptotic rates and enhanced vascular alterations in the former. Notably, they also revealed increased levels of membrane-bound phosphorylated AKT, suggestive of enhanced glycolysis, and alterations in mitochondrial sub-cellular distribution. Both characteristics are common metabolic adaptations in primary tumors. These data together with reduced mtDNA copy number and elevated levels of the mitochondrial antioxidant PRX3 in cancer tissue samples suggest the presence of mitochondrial oxidative stress. In plasma, cancer patients showed higher levels of cfDNA and mtDNA. Of note, mtDNA plasma levels inversely correlated with those in the tissue, suggesting that higher death rates were linked to lower mtDNA copy number. In PBMCs, cancer patients showed higher levels of PGC-1α, a positive regulator of mitochondrial function, but this increase was not associated with a corresponding induction of its target genes, suggesting a reduced activity in cancer patients. We also observed a significant difference in the PRDX3/PFKFB3 correlation at the gene expression level, between carcinoma and hyperplasia patients, also indicative of increased systemic metabolic stress in cancer patients. The correlation of mtDNA levels in tissue and PBMCs further stressed the interconnection between systemic and tumor metabolism. Evaluation of the mitochondrial gene ND1 in plasma, PBMCs and tissue samples, suggested that it could be a good biomarker for systemic oxidative metabolism, with ND1/mtDNA ratio positively correlating in PBMCs and tissue samples. In contrast, ND4 evaluation would be informative of tumor development, with ND4/mtDNA ratio specifically altered in the tumor context. Taken together, our data suggest that metabolic dysregulation in thyroid cancer can be monitored accurately in blood samples and might be exploited for the accurate discrimination of cancer from hyperplasia.
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14
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Abou Karam G, Malhotra A. PET/CT May Assist in Avoiding Pointless Thyroidectomy in Indeterminate Thyroid Nodules: A Narrative Review. Cancers (Basel) 2023; 15:cancers15051547. [PMID: 36900338 PMCID: PMC10000406 DOI: 10.3390/cancers15051547] [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: 01/21/2023] [Revised: 02/23/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
Indeterminate thyroid nodules (ITN) are commonly encountered among the general population, with a malignancy rate of 10 to 40%. However, many patients may be overtreated with futile surgery for benign ITN. To avoid unnecessary surgery, PET/CT scan is a possible alternative to help differentiate between benign and malignant ITN. In this narrative review, the major results and limitations of the most recent studies on PET/CT efficacy (from PET/CT visual assessment to quantitative PET parameters and recent radiomic features analysis) and on cost-effectiveness (compared to other alternatives (such as surgery)) are presented. PET/CT can reduce futile surgery with visual assessment (around 40%; if ITN ≥ 10 mm). Moreover, PET/CT conventional parameters and radiomic features extracted from PET/CT imaging can be associated together in a predictive model to rule out malignancy in ITN, with a high NPV (96%) when certain criteria are met. Even though promising results were obtained in these recent PET/CT studies, further studies are needed to enable PET/CT to become the definitive diagnostic tool once a thyroid nodule is identified as indeterminate.
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Affiliation(s)
- Gaby Abou Karam
- Section of Neuroradiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St., New Haven, CT 06510, USA
| | - Ajay Malhotra
- Section of Neuroradiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St., New Haven, CT 06510, USA
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 789 Howard Ave, New Haven, CT 06519, USA
- Correspondence: ; Tel.: +1-(203)-785-5102; Fax: +1-(203)-737-1077
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15
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Dong XC, Liu C, Zhuo GC, Ding Y. Potential Roles of mtDNA Mutations in PCOS-IR: A Review. Diabetes Metab Syndr Obes 2023; 16:139-149. [PMID: 36760584 PMCID: PMC9884460 DOI: 10.2147/dmso.s393960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disease that affecting females in reproductive age. Insulin resistance (IR), an important molecular basis for PCOS, accounts for at least 75% of women carrying this syndrome. Although there have been many studies on PCOS-IR, the detailed mechanisms are not fully understood. As essential hub for energy generation, mitochondria are critical to insulin secretion and normal function, whereas mutations in mitochondrial DNA (mtDNA) result in mitochondrial dysfunctions contributing to the pathophysiology of PCOS-IR via the regulation of balance of oxidative stress (OS), energy deficiency, or hormone metabolism. In the current review, we summarize the clinical and molecular features of PCOS-IR and discuss molecular mechanisms related to mtDNA mutations.
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Affiliation(s)
- Xiao-Chao Dong
- Department of Gynecology and Obstetrics, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Chang Liu
- Department of Gynecology and Obstetrics, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Guang-Chao Zhuo
- Central Laboratory, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yu Ding
- Central Laboratory, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
- Correspondence: Yu Ding, Central Laboratory, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, People’s Republic of China, Tel/Fax +86-571-5600-5600, Email
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16
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Akbulut S, Yagin FH, Colak C. Prediction of Breast Cancer Distant Metastasis by Artificial Intelligence Methods from an Epidemiological Perspective. ISTANBUL MEDICAL JOURNAL 2022. [DOI: 10.4274/imj.galenos.2022.62443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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17
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Smith ALM, Whitehall JC, Greaves LC. Mitochondrial
DNA
mutations in aging and cancer. Mol Oncol 2022; 16:3276-3294. [PMID: 35842901 PMCID: PMC9490137 DOI: 10.1002/1878-0261.13291] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/18/2022] [Accepted: 07/15/2022] [Indexed: 11/09/2022] Open
Abstract
Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age‐related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.
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Affiliation(s)
- Anna LM Smith
- Wellcome Centre for Mitochondrial Research, Biosciences Institute Newcastle University Newcastle Upon Tyne NE2 4HH UK
| | - Julia C Whitehall
- Wellcome Centre for Mitochondrial Research, Biosciences Institute Newcastle University Newcastle Upon Tyne NE2 4HH UK
| | - Laura C Greaves
- Wellcome Centre for Mitochondrial Research, Biosciences Institute Newcastle University Newcastle Upon Tyne NE2 4HH UK
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18
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Abi-Raad R, Prasad ML, Adeniran AJ, Cai G. Copy number variations identified in thyroid FNA specimens are associated with Hürthle cell cytomorphology. Cancer Cytopathol 2022; 130:415-422. [PMID: 35332982 DOI: 10.1002/cncy.22569] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/29/2021] [Accepted: 01/05/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND The fine-needle aspiration (FNA) diagnosis of thyroid Hürthle cell neoplasms (HCNs) remains challenging. This study explored a possible association of copy number variations (CNVs) with Hürthle cell lesions of the thyroid. METHODS Thyroid FNA cases that were diagnosed as follicular lesion of undetermined significance (FLUS) or follicular neoplasm (FN)/HCN for which the ThyroSeq version 3 genomic classifier test was performed were retrieved. RESULTS A total of 324 thyroid FNA cases (228 FLUS cases, 46 HCN cases, and 50 FN cases) were included in the study. FLUS cases were further classified as Hürthle cell type (follicular lesion of undetermined significance-Hürthle cell type [FLUS-HCT]; 20 cases) or non-Hürthle cell type (follicular lesion of undetermined significance-non-Hürthle cell type [FLUS-NHCT]; 208 cases). HCN and FLUS-HCT cases showed a higher prevalence of CNVs (23 of 66 [35%]) in comparison with those classified as FN or FLUS-NHCT (14 of 258 [5%]; P < .001). A total of 105 patients had histopathologic follow-up. Cases with CNVs were more likely to be neoplastic (18 of 26 [69%]) and associated with Hürthle cell changes (14 of 26 [54%]) in comparison with cases without any molecular alterations (neoplastic, 8 of 24 [33%]; Hürthle cell changes, 2 of 24 [8%]; P < .05). In HCN/FLUS-HCT cases with CNVs (n = 14), Hürthle cell changes (13 of 14 [93%]) and neoplasms (9 of 14 [64%]) were more likely to be seen on surgical follow-up in comparison with the 17 cases without CNVs (Hürthle cell changes, 6 of 17 [35%]; neoplastic, 3 of 17 [18%]; P < .05). CONCLUSIONS CNVs identified in thyroid FNA cases are associated with Hürthle cell morphology and are suggestive of a neoplasm with Hürthle cell features in thyroid FNAs classified as FLUS-HCT/HCN. This finding may be helpful in triaging patients who would benefit from surgical management.
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Affiliation(s)
- Rita Abi-Raad
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Manju L Prasad
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Adebowale J Adeniran
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Guoping Cai
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
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19
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Thyroid Cancer-Associated Mitochondrial DNA Mutation G3842A Promotes Tumorigenicity via ROS-Mediated ERK1/2 Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9982449. [PMID: 35464760 PMCID: PMC9020963 DOI: 10.1155/2022/9982449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/09/2021] [Accepted: 01/27/2022] [Indexed: 11/17/2022]
Abstract
Mitochondrial DNA (mtDNA) mutations have been identified in various human cancers, including thyroid cancer. However, the relationship between mtDNA and thyroid cancer remains unclear. Previous studies by others and us strongly suggested that mtDNA mutations in complex I may participate in thyroid cancer processes according to sequencing results of thyroid cancer tissue, although the associated pathogenic processes remain unknown. Here, to investigate whether mtDNA mutations contribute to thyroid cancer, we reanalyzed our sequencing results and characterized thyroid cancer-associated mutations in the mitochondrial complex. The results identified the highest mutation frequencies in nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase subunit 4 gene (ND4) and cytochrome c oxidase subunit 1 gene (COI), which also harbored the highest rates of
substitutions, with most of the mutations resulting in changes in the polarity of amino acids. We then established cybrids containing the G3842A mutation identified in papillary thyroid carcinoma, which revealed it as a mutation in NADH dehydrogenase subunit 1 gene (ND1) and is previously reported in follicular thyroid carcinoma, thereby suggesting a possibly pathogenic role in thyroid carcinoma. Additionally, we found that the G3842A mutation accelerates tumorigenicity and decreases the abundance and activity of mitochondrial complex I, the oxygen consumption rate, and adenosine triphosphate levels. By contrast, the levels of reactive oxygen species (ROS) were increased to activate extracellular signal-regulated kinase (ERK1/2) signaling, which contributed to tumorigenicity. These findings suggest for the first time that mtDNA mutations help drive tumor development and that G3842A may represent a new risk factor for thyroid cancer. Furthermore, our findings indicate that drugs targeting ROS and ERK1/2 may serve as a viable therapeutic strategy for thyroid cancer.
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20
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Hönigova K, Navratil J, Peltanova B, Polanska HH, Raudenska M, Masarik M. Metabolic tricks of cancer cells. Biochim Biophys Acta Rev Cancer 2022; 1877:188705. [PMID: 35276232 DOI: 10.1016/j.bbcan.2022.188705] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/11/2022] [Accepted: 02/26/2022] [Indexed: 12/15/2022]
Abstract
One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.
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Affiliation(s)
- Katerina Hönigova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Jiri Navratil
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Barbora Peltanova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Hana Holcova Polanska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Martina Raudenska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Michal Masarik
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic.
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21
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Tarabichi M, Demetter P, Craciun L, Maenhaut C, Detours V. Thyroid cancer under the scope of emerging technologies. Mol Cell Endocrinol 2022; 541:111491. [PMID: 34740746 DOI: 10.1016/j.mce.2021.111491] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/08/2021] [Accepted: 10/18/2021] [Indexed: 01/03/2023]
Abstract
The vast majority of thyroid cancers originate from follicular cells. We outline outstanding issues at each step along the path of cancer patient care, from prevention to post-treatment follow-up and highlight how emerging technologies will help address them in the coming years. Three directions will dominate the coming technological landscape. Genomics will reveal tumoral evolutionary history and shed light on how these cancers arise from the normal epithelium and the genomics alteration driving their progression. Transcriptomics will gain cellular and spatial resolution providing a full account of intra-tumor heterogeneity and opening a window on the microenvironment supporting thyroid tumor growth. Artificial intelligence will set morphological analysis on an objective quantitative ground laying the foundations of a systematic thyroid tumor classification system. It will also integrate into unified representations the molecular and morphological perspectives on thyroid cancer.
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Affiliation(s)
- Maxime Tarabichi
- Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
| | - Pieter Demetter
- Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Ligia Craciun
- Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Carine Maenhaut
- Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
| | - Vincent Detours
- Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
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22
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Peng Y, Liu H, Liu J, Long J. Post-translational modifications on mitochondrial metabolic enzymes in cancer. Free Radic Biol Med 2022; 179:11-23. [PMID: 34929314 DOI: 10.1016/j.freeradbiomed.2021.12.264] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/26/2021] [Accepted: 12/15/2021] [Indexed: 12/22/2022]
Abstract
Mitochondrion is the powerhouse of the cell. The research of nearly a century has expanded our understanding of mitochondrion, far beyond the view that mitochondrion is an important energy generator of cells. During the initiation, growth and survival of tumor cells, significant mitochondrial metabolic changes have taken place in the important enzymes of respiratory chain and tricarboxylic acid cycle, mitochondrial biogenesis and dynamics, oxidative stress regulation and molecular signaling. Therefore, mitochondrial metabolic proteins are the key mediators of tumorigenesis. Post-translational modification is the molecular switch that regulates protein function. Understanding how these mitochondria-related post-translational modification function during tumorigenesis will bring new ideas for the next generation of cancer treatment.
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Affiliation(s)
- Yunhua Peng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Huadong Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China; University of Health and Rehabilitation Sciences, Qingdao, 266071, China
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
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23
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Abstract
The molecular signatures of many thyroid tumors have been uncovered. These discoveries have translated into clinical practice and are changing diagnostic and tumor classification paradigms. Here, the findings of recent studies are presented with special emphasis on how molecular insights are impacting the understating of RAS mutant thyroid nodules, Hürthel cell neoplasms, and unusual thyroid tumors, such as hyalinizing trabecular tumor, secretory carcinoma of the thyroid, and sclerosing mucoepidermoid carcinoma with eosinophilia. In addition, the utility of detecting actionable molecular alterations by immunohistochemistry in advanced and aggressive thyroid cancer is also discussed.
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Affiliation(s)
- Juan C Hernandez-Prera
- Department of Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
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24
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Lima AR, Correia M, Santos L, Tavares C, Rios E, Canberk S, Soares P, Sobrinho-Simões M, Melo M, Máximo V. S616-p-DRP1 associates with locally invasive behavior of follicular cell-derived thyroid carcinoma. Endocrine 2021; 73:85-97. [PMID: 33219495 DOI: 10.1007/s12020-020-02546-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/02/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC). METHODS Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals. RESULTS DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028). CONCLUSIONS S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.
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Affiliation(s)
- Ana Rita Lima
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.
- Faculty of Medicine of the University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal.
| | - Marcelo Correia
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
| | - Liliana Santos
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- CIBB Consortium, University of Coimbra, Coimbra, Portugal
| | - Catarina Tavares
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
| | - Elisabete Rios
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Pathology, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Sule Canberk
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal
- Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
| | - Paula Soares
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Manuel Sobrinho-Simões
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Pathology, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Miguel Melo
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra (CHUC), Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal
- Faculty of Medicine of the University of Coimbra (FMUC), Rua Larga, 3004-504, Coimbra, Portugal
| | - Valdemar Máximo
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal
- Cancer Signaling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
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The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy. Cells 2021; 10:cells10051082. [PMID: 34062862 PMCID: PMC8147376 DOI: 10.3390/cells10051082] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 12/13/2022] Open
Abstract
Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.
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Titov SE, Kozorezova ES, Demenkov PS, Veryaskina YA, Kuznetsova IV, Vorobyev SL, Chernikov RA, Sleptsov IV, Timofeeva NI, Ivanov MK. Preoperative Typing of Thyroid and Parathyroid Tumors with a Combined Molecular Classifier. Cancers (Basel) 2021; 13:cancers13020237. [PMID: 33440616 PMCID: PMC7827881 DOI: 10.3390/cancers13020237] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/06/2023] Open
Abstract
In previous studies, we described a method for detecting and typing malignant tumors of the thyroid gland in fine-needle aspiration biopsy samples via analysis of a molecular marker panel (normalized HMGA2 mRNA level; normalized microRNA-146b, -221, and -375 levels; mitochondrial-to-nuclear DNA ratio; and BRAFV600E mutation) in cytological preparations by quantitative PCR. In the present study, we aimed to estimate the specificity of the typing of different thyroid tumors by the proposed method. Fine-needle aspiration cytological preparations from 278 patients were used. The histological diagnosis was known for each sample. The positive and negative predictive values of the method assessed in this study were, respectively, 100% and 98% for papillary thyroid carcinoma (n = 63), 100% and 100% for medullary thyroid carcinoma (n = 19), 43.5% and 98% for follicular carcinoma (n = 15), and 86% and 100% for Hürthle cell carcinoma (n = 6). Thus, we demonstrate that the diagnostic panel, including the analysis of microRNA expression, mRNA expression, the BRAFV600E mutation, and the mitochondrial-to-nuclear DNA ratio, allows the highly accurate identification of papillary thyroid carcinoma, medullary thyroid carcinoma, and Hürthle cell carcinoma but not malignant follicular tumors (positive predictive value was below 50%).
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Affiliation(s)
- Sergei E. Titov
- Department of the Structure and Function of Chromosomes, Institute of Molecular and Cellular Biology, SB RAS, 630090 Novosibirsk, Russia; (Y.A.V.); (M.K.I.)
- AO Vector-Best, 630117 Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia;
- Correspondence:
| | - Evgeniya S. Kozorezova
- National Center of Clinical Morphological Diagnostics, 192283 Saint Petersburg, Russia; (E.S.K.); (I.V.K.); (S.L.V.); (R.A.C.); (N.I.T.)
- Institute of Molecular Pathology and Pathomorphology, 630117 Novosibirsk, Russia
| | - Pavel S. Demenkov
- Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia;
- Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia
| | - Yulia A. Veryaskina
- Department of the Structure and Function of Chromosomes, Institute of Molecular and Cellular Biology, SB RAS, 630090 Novosibirsk, Russia; (Y.A.V.); (M.K.I.)
- Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia
| | - Irina V. Kuznetsova
- National Center of Clinical Morphological Diagnostics, 192283 Saint Petersburg, Russia; (E.S.K.); (I.V.K.); (S.L.V.); (R.A.C.); (N.I.T.)
| | - Sergey L. Vorobyev
- National Center of Clinical Morphological Diagnostics, 192283 Saint Petersburg, Russia; (E.S.K.); (I.V.K.); (S.L.V.); (R.A.C.); (N.I.T.)
| | - Roman A. Chernikov
- National Center of Clinical Morphological Diagnostics, 192283 Saint Petersburg, Russia; (E.S.K.); (I.V.K.); (S.L.V.); (R.A.C.); (N.I.T.)
| | - Ilya V. Sleptsov
- Department of Endocrinology and Endocrine Surgery of Saint Petersburg State University N.I. Pirogov Clinic of High Medical Technologies, 190103 Saint Petersburg, Russia;
| | - Nataliya I. Timofeeva
- National Center of Clinical Morphological Diagnostics, 192283 Saint Petersburg, Russia; (E.S.K.); (I.V.K.); (S.L.V.); (R.A.C.); (N.I.T.)
| | - Mikhail K. Ivanov
- Department of the Structure and Function of Chromosomes, Institute of Molecular and Cellular Biology, SB RAS, 630090 Novosibirsk, Russia; (Y.A.V.); (M.K.I.)
- AO Vector-Best, 630117 Novosibirsk, Russia
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Correia M, Lima AR, Batista R, Máximo V, Sobrinho-Simões M. Inherited Thyroid Tumors With Oncocytic Change. Front Endocrinol (Lausanne) 2021; 12:691979. [PMID: 34177813 PMCID: PMC8220141 DOI: 10.3389/fendo.2021.691979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/12/2021] [Indexed: 01/19/2023] Open
Abstract
Familial non-medullary thyroid carcinoma (FNMTC) corresponds to 5-10% of all follicular cell-derived carcinoma (FCDTC). Oncocytic thyroid tumors have an increased incidence in the familial context in comparison with sporadic FCDTC, encompassing benign and malignant tumors in the same family presenting with some extent of cell oxyphilia. This has triggered the interest of our and other groups to clarify the oncocytic change, looking for genetic markers that could explain the emergence of this phenotype in thyroid benign and malignant lesions, focusing on familial aggregation. Despite some advances regarding the identification of the gene associated with retinoic and interferon-induced mortality 19 (GRIM-19), as one of the key candidate genes affected in the "Tumor with Cell Oxyphilia" (TCO) locus, most of the mutations follow a pattern of "private mutations", almost exclusive to one family. Moreover, no causative genetic alterations were identified so far in most families. The incomplete penetrance of the disease, the diverse benign and malignant phenotypes in the affected familial members and the variable syndromic associations create an additional layer of complexity for studying the genetic alterations in oncocytic tumors. In the present review, we summarized the available evidence supporting genomic-based mechanisms for the oncocytic change, particularly in the context of FNMTC. We have also addressed the challenges and gaps in the aforementioned mechanisms, as well as molecular clues that can explain, at least partially, the phenotype of oncocytic tumors and the respective clinico-pathological behavior. Finally, we pointed to areas of further investigation in the field of oncocytic (F)NMTC with translational potential in terms of therapy.
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Affiliation(s)
- Marcelo Correia
- Cancer Signalling and Metabolism, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Cancer Signalling and Metabolism, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- *Correspondence: Marcelo Correia,
| | - Ana Rita Lima
- Cancer Signalling and Metabolism, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Cancer Signalling and Metabolism, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Rui Batista
- Cancer Signalling and Metabolism, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Cancer Signalling and Metabolism, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Valdemar Máximo
- Cancer Signalling and Metabolism, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Cancer Signalling and Metabolism, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Manuel Sobrinho-Simões
- Cancer Signalling and Metabolism, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Cancer Signalling and Metabolism, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Department of Pathology, Centro Hospitalar e Universitário São João (CHUSJ), Porto, Portugal
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Abstract
Oncocytes are cells that have abundant eosinophilic cytoplasm due to the accumulation of mitochondria; they are also known as oxyphils. In the thyroid they have been called Hürthle cells but this is a misnomer, since Hürthle described C cells; for this reason, we propose the use of "oncocyte" as a scientific term rather than an incorrect eponym. Oncocytic change occurs in nontumorous thyroid disorders, in benign and malignant tumors of thyroid follicular cells, in tumors composed of thyroid C cells, and intrathyroidal parathyroid proliferations as well as in metastatic lesions. The morphology of primary oncocytic thyroid tumors is similar to that of their non-oncocytic counterparts but also is complicated by the cytologic features of these cells that include both abundant eosinophilic cytoplasm and large cherry red nucleoli. The molecular alterations in oncocytic thyroid tumors echo those of their non-oncocytic counterparts but in addition feature mitochondrial DNA mutations as well as chromosomal gains and losses. In this review we emphasize the importance of recognition of the spectrum of oncocytic thyroid pathology. The cell of origin, morphologic features including architecture, nuclear atypia and invasive growth, as well as high grade features such as mitoses and necrosis, enable accurate classification of these lesions. The molecular alterations underlying the pathological entity are associated with genetic alterations associated with oncocytic change. The arbitrary cut-off of 75% oncocytic change to classify a lesion as an oncocytic variant brings another complexity to the classification scheme of tumors that frequently have mixed oncocytic and non-oncocytic components. This controversial and often confusing area of thyroid pathology requires thoughtful and cautious investigation to clarify accurate diagnosis, prognosis and prediction for patients with oncocytic thyroid lesions.
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Affiliation(s)
- Sylvia L. Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
- Department of Pathology, University Health Network, Toronto, ON, Canada
- *Correspondence: Sylvia L. Asa, ; Ozgur Mete,
| | - Ozgur Mete
- Department of Pathology, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- *Correspondence: Sylvia L. Asa, ; Ozgur Mete,
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Polymorphisms and haplotype of mitochondrial DNA D-loop region are associated with polycystic ovary syndrome in a Chinese population. Mitochondrion 2020; 57:173-181. [PMID: 33385542 DOI: 10.1016/j.mito.2020.12.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/16/2020] [Accepted: 12/16/2020] [Indexed: 01/29/2023]
Abstract
Polymorphisms in mitochondrial DNA (mtDNA) have been linked to a range of diseases. Here we investigate the relationship between mtDNA D-loop region polymorphisms, mtDNA haplotype and polycystic ovary syndrome (PCOS), as well as the correlation of D-loop variants and clinical characteristics of PCOS, in a Chinese population. The mtDNA D-loop of whole blood samples from 421 PCOS patients and 409 controls underwent next generation sequencing. The variants G207A (PBH＜0.05), 16036GGins (PBH＜0.05) and 16049Gins (PBH＜0.001) were associated with decreased risk of PCOS. No variants were associated with PCOS, and within the PCOS group, no statistical significance was found between D-loop polymorphisms and clinical characteristics. Patient haplotype was identified from D-loop single nucleotide polymorphisms and analysis suggested that haplotype A15 (P adjusted ＜0.01) was significantly associated with decreased risk of PCOS. In conclusion, mtDNA D-loop alterations and haplotype appear to confer resistance to PCOS in Chinese women.
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Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features. Cancers (Basel) 2020; 13:cancers13010026. [PMID: 33374707 PMCID: PMC7793513 DOI: 10.3390/cancers13010026] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/11/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Hürthle cell carcinoma (HCC) represents 3–4% of thyroid carcinoma cases. It is characterized by its large, granular and eosinophilic cytoplasm, due to an excessive number of mitochondria. Hürthle cells can be identified only after fine needle aspiration cytology biopsy or by histological diagnosis after the surgical operation. Published studies on HCC indicate its putative high aggressiveness. In this article, current knowledge of HCC focusing on clinical features, cytopathological features, genetic changes, as well as pitfalls in diagnosis are reviewed in order to improve clinical management. Abstract Hürthle cell carcinoma (HCC) represents 3–4% of thyroid carcinoma cases. It is considered to be more aggressive than non-oncocytic thyroid carcinomas. However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. The Hürthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. Cytoplasmic granularity is due to the presence of numerous mitochondria. These mitochondria display packed stacking cristae and are arranged in the center. HCC is more often observed in females in their 50–60s. Preoperative diagnosis is challenging, but indicators of malignancy are male, older age, tumor size > 4 cm, a solid nodule with an irregular border, or the presence of psammoma calcifications according to ultrasound. Thyroid lobectomy alone is sufficient treatment for small, unifocal, intrathyroidal carcinomas, or clinically detectable cervical nodal metastases, but total thyroidectomy is recommended for tumors larger than 4 cm. The effectiveness of radioactive iodine is still debated. Molecular changes involve cellular signaling pathways and mitochondria-related DNA. Current knowledge of Hürthle cell carcinoma, including clinical, pathological, and molecular features, with the aim of improving clinical management, is reviewed.
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31
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Bai Y, Kakudo K, Jung CK. Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification. Endocrinol Metab (Seoul) 2020; 35:696-715. [PMID: 33261309 PMCID: PMC7803616 DOI: 10.3803/enm.2020.807] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/23/2020] [Indexed: 12/12/2022] Open
Abstract
Advances in medical sciences and evidence-based medicine have led to momentous changes in classification and management of thyroid neoplasms. Much progress has been made toward avoiding overdiagnosis and overtreatment of thyroid cancers. The new 2017 World Health Organization (WHO) classification of thyroid neoplasms updated the diagnostic criteria and molecular and genetic characteristics reflecting the biology and behavior of the tumors, and newly introduced the category of borderline malignancy or uncertain malignant potential. Some neoplasms were subclassified, renamed, or redefined as a specific entity. This review introduces changes in the fourth edition WHO classification of thyroid tumors and updates the contemporary diagnosis and classification of thyroid tumors. We also discuss several challenges with the proposal of new diagnostic entities, since they have unique histopathologic and molecular features and clinical relevance.
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Affiliation(s)
- Yanhua Bai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing,
China
| | - Kennichi Kakudo
- Department of Pathology and Thyroid Disease Center, Izumi City General Hospital, Izumi,
Japan
- Department of Human Pathology, Wakayama Medical University, Graduate School of Medicine, Wakayama,
Japan
| | - Chan Kwon Jung
- Department of Hospital Pathology, The Catholic University of Korea, Seoul,
Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul,
Korea
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Wong KS, Angell TE, Barletta JA, Krane JF. Hürthle cell lesions of the thyroid: Progress made and challenges remaining. Cancer Cytopathol 2020; 129:347-362. [PMID: 33108684 DOI: 10.1002/cncy.22375] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 12/31/2022]
Abstract
Hürthle cell-predominant thyroid fine needle aspirations (FNA) are encountered frequently in routine practice, yet they are often challenging to diagnose accurately and are associated with significant interobserver variability. This is largely due to the ubiquity of Hürthle cells in thyroid pathology, ranging from nonneoplastic conditions to aggressive malignancies. Although limitations in cytomorphologic diagnoses likely will remain for the foreseeable future, our knowledge of the molecular pathogenesis of Hürthle cell neoplasia and application of molecular testing to cytologic material have increased dramatically within the past decade. This review provides context behind the challenges in diagnosis of Hürthle cell lesions and summarizes the more recent advances in diagnostic tools.
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Affiliation(s)
- Kristine S Wong
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Trevor E Angell
- Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Justine A Barletta
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jeffrey F Krane
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
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33
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Galber C, Acosta MJ, Minervini G, Giorgio V. The role of mitochondrial ATP synthase in cancer. Biol Chem 2020; 401:1199-1214. [PMID: 32769215 DOI: 10.1515/hsz-2020-0157] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/27/2020] [Indexed: 12/19/2022]
Abstract
The mitochondrial ATP synthase is a multi-subunit enzyme complex located in the inner mitochondrial membrane which is essential for oxidative phosphorylation under physiological conditions. In this review, we analyse the enzyme functions involved in cancer progression by dissecting specific conditions in which ATP synthase contributes to cancer development or metastasis. Moreover, we propose the role of ATP synthase in the formation of the permeability transition pore (PTP) as an additional mechanism which controls tumour cell death. We further describe transcriptional and translational modifications of the enzyme subunits and of the inhibitor protein IF1 that may promote adaptations leading to cancer metabolism. Finally, we outline ATP synthase gene mutations and epigenetic modifications associated with cancer development or drug resistance, with the aim of highlighting this enzyme complex as a potential novel target for future anti-cancer therapy.
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Affiliation(s)
- Chiara Galber
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, V.le G. Colombo 3, I-35121, Padova, Italy
- Department of Biomedical Sciences, University of Padova, I-35121, Padova, Italy
| | - Manuel Jesus Acosta
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, V.le G. Colombo 3, I-35121, Padova, Italy
- Department of Biomedical Sciences, University of Padova, I-35121, Padova, Italy
| | - Giovanni Minervini
- Department of Biomedical Sciences, University of Padova, I-35121, Padova, Italy
| | - Valentina Giorgio
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, V.le G. Colombo 3, I-35121, Padova, Italy
- Department of Biomedical Sciences, University of Padova, I-35121, Padova, Italy
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Fendt L, Fazzini F, Weissensteiner H, Bruckmoser E, Schönherr S, Schäfer G, Losso JL, Streiter GA, Lamina C, Rasse M, Klocker H, Kofler B, Kloss-Brandstätter A, Huck CW, Kronenberg F, Laimer J. Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study. Cancers (Basel) 2020; 12:E1933. [PMID: 32708892 PMCID: PMC7409097 DOI: 10.3390/cancers12071933] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 01/25/2023] Open
Abstract
While a shift in energy metabolism is essential to cancers, the knowledge about the involvement of the mitochondrial genome in tumorigenesis and progression in oral squamous cell carcinoma (OSCC) is still very limited. In this study, we evaluated 37 OSCC tumors and the corresponding benign mucosa tissue pairs by deep sequencing of the complete mitochondrial DNA (mtDNA). After extensive quality control, we identified 287 variants, 137 in tumor and 150 in benign samples exceeding the 1% threshold. Variant heteroplasmy levels were significantly increased in cancer compared to benign tissues (p = 0.0002). Furthermore, pairwise high heteroplasmy frequency difference variants (∆HF% > 20) with potential functional impact were increased in the cancer tissues (p = 0.024). Fourteen mutations were identified in the protein-coding region, out of which thirteen were detected in cancer and only one in benign tissue. After eight years of follow-up, the risk of mortality was higher for patients who harbored at least one ∆HF% > 20 variant in mtDNA protein-coding regions relative to those with no mutations (HR = 4.6, (95%CI = 1.3-17); p = 0.019 in primary tumor carriers). Haplogroup affiliation showed an impact on survival time, which however needs confirmation in a larger study. In conclusion, we observed a significantly higher accumulation of somatic mutations in the cancer tissues associated with a worse prognosis.
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Affiliation(s)
- Liane Fendt
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Federica Fazzini
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Hansi Weissensteiner
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Emanuel Bruckmoser
- Oral and Maxillofacial Surgeon, Private Practice, A-5020 Salzburg, Austria;
| | - Sebastian Schönherr
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Georg Schäfer
- Institute for Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
| | - Jamie Lee Losso
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Gertraud A. Streiter
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Claudia Lamina
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Michael Rasse
- University Hospital for Craniomaxillofacial and Oral Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
- Clinic for Maxillofacial Surgery, Sechenov University, Trubetskaya Str. 8 b.2, 119992 Moscow, Russia
| | - Helmut Klocker
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
| | - Barbara Kofler
- Department of Otorhinolaryngology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria;
| | - Anita Kloss-Brandstätter
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
- Carinthia University of Applied Sciences, A-9524 Villach, Austria
| | - Christian W. Huck
- Institute of Analytical Chemistry and Radiochemistry, CCB-Center for Chemistry and Biomedicine, Leopold Franzens University Innsbruck, A-6020 Innsbruck, Austria;
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; (L.F.); (F.F.); (H.W.); (S.S.); (J.L.L.); (G.A.S.); (C.L.); (A.K.-B.); (F.K.)
| | - Johannes Laimer
- University Hospital for Craniomaxillofacial and Oral Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
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Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis. Int J Mol Sci 2020; 21:ijms21145040. [PMID: 32708855 PMCID: PMC7404335 DOI: 10.3390/ijms21145040] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die in circulation, the survival of a few CTCs can seed the development of a tumor at a secondary location. An increasing number of studies demonstrate that CTCs undergo modification in response to the dynamic biophysical environment in the blood due in part to fluid shear stress. Fluid shear stress generates reactive oxygen species (ROS), triggers redox-sensitive cell signaling, and alters the function of intracellular organelles. In particular, the mitochondrion is an important target organelle in determining the metastatic phenotype of CTCs. In healthy cells, mitochondria produce adenosine triphosphate (ATP) via oxidative phosphorylation in the electron transport chain, and during oxidative phosphorylation, they produce physiological levels of ROS. Mitochondria also govern death mechanisms such as apoptosis and mitochondrial permeability transition pore opening to, in order eliminate unwanted or damaged cells. However, in cancer cells, mitochondria are dysregulated, causing aberrant energy metabolism, redox homeostasis, and cell death pathways that may favor cancer invasiveness. In this review, we discuss the influence of fluid shear stress on CTCs with an emphasis on breast cancer pathology, then discuss alterations of cellular mechanisms that may increase the metastatic potentials of CTCs.
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San Román Gil M, Pozas J, Molina-Cerrillo J, Gómez J, Pian H, Pozas M, Carrato A, Grande E, Alonso-Gordoa T. Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy. Int J Mol Sci 2020; 21:E4951. [PMID: 32668761 PMCID: PMC7403957 DOI: 10.3390/ijms21144951] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 07/10/2020] [Indexed: 12/16/2022] Open
Abstract
Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.
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MESH Headings
- Adenocarcinoma, Follicular/enzymology
- Adenocarcinoma, Follicular/genetics
- Adenocarcinoma, Follicular/therapy
- Adenoma, Oxyphilic/enzymology
- Adenoma, Oxyphilic/genetics
- Adenoma, Oxyphilic/therapy
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Medullary/enzymology
- Carcinoma, Medullary/genetics
- Carcinoma, Medullary/therapy
- Carcinoma, Papillary/enzymology
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/therapy
- Clinical Trials as Topic
- Combined Modality Therapy
- Disease Management
- Forecasting
- Genes, Neoplasm
- Humans
- Immune Checkpoint Inhibitors/therapeutic use
- Immunoconjugates/therapeutic use
- Immunotherapy
- Iodine Radioisotopes/therapeutic use
- Molecular Targeted Therapy
- Multicenter Studies as Topic
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Oncogene Proteins, Fusion/antagonists & inhibitors
- Oncogene Proteins, Fusion/genetics
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Protein-Tyrosine Kinases/genetics
- Randomized Controlled Trials as Topic
- Thyroid Neoplasms/enzymology
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/therapy
- Tumor Microenvironment/immunology
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Affiliation(s)
- María San Román Gil
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (M.S.R.G.); (J.P.); (M.P.); (A.C.); (T.A.-G.)
| | - Javier Pozas
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (M.S.R.G.); (J.P.); (M.P.); (A.C.); (T.A.-G.)
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (M.S.R.G.); (J.P.); (M.P.); (A.C.); (T.A.-G.)
- The Ramon y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain; (J.G.); (H.P.)
| | - Joaquín Gómez
- Medicine School, Alcalá University, 28805 Madrid, Spain; (J.G.); (H.P.)
- General Surgery Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Héctor Pian
- Medicine School, Alcalá University, 28805 Madrid, Spain; (J.G.); (H.P.)
- Pathology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Miguel Pozas
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (M.S.R.G.); (J.P.); (M.P.); (A.C.); (T.A.-G.)
| | - Alfredo Carrato
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (M.S.R.G.); (J.P.); (M.P.); (A.C.); (T.A.-G.)
- The Ramon y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain; (J.G.); (H.P.)
| | - Enrique Grande
- Medical Oncology Department, MD Anderson Cancer Center, 28033 Madrid, Spain;
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (M.S.R.G.); (J.P.); (M.P.); (A.C.); (T.A.-G.)
- The Ramon y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain; (J.G.); (H.P.)
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37
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The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Ann Surg 2020; 271:e21-e93. [PMID: 32079830 DOI: 10.1097/sla.0000000000003580] [Citation(s) in RCA: 273] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. BACKGROUND Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. METHODS The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSIONS Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.
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38
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Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol 2020; 16:316-333. [PMID: 32393826 DOI: 10.1038/s41584-020-0413-5] [Citation(s) in RCA: 496] [Impact Index Per Article: 99.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2020] [Indexed: 12/31/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.
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Affiliation(s)
- Gyrid Nygaard
- Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, San Diego, CA, USA
| | - Gary S Firestein
- Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, San Diego, CA, USA.
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39
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Jalaly JB, Baloch ZW. Hürthle-cell neoplasms of the thyroid: An algorithmic approach to pathologic diagnosis in light of molecular advances. Semin Diagn Pathol 2020; 37:234-242. [PMID: 32444244 DOI: 10.1053/j.semdp.2020.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/13/2020] [Accepted: 03/23/2020] [Indexed: 01/17/2023]
Abstract
Our understanding of neoplasia is evolving at a rapid pace in these exciting times, where recent molecular pathology advances are reinforcing and fine tuning morphological divisions and classification. Thyroid gland neoplasia in general, and Hürthle-cell neoplasms in particular, are no exception in the current era of histopathology-molecular biology paradigm. In this review paper, we discuss the rationale that led pathologists in the past to separate Hürthle-cell neoplasms into its own dedicated diagnostic category, and provide an algorithmic approach to the differential diagnosis of oncocytic lesions of the thyroid. This review will also shed light on the current WHO classification of Hürthle-cell neoplasms in light of molecular advances that justify histopathologic distinctions.
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Affiliation(s)
- Jalal B Jalaly
- Hospital of the University of Pennsylvania, Department of Pathology, Philadelphia, (PA), United States
| | - Zubair W Baloch
- Hospital of the University of Pennsylvania, Department of Pathology, Philadelphia, (PA), United States.
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40
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Abstract
Mitochondria play various important roles in energy production, metabolism, and apoptosis. Mitochondrial dysfunction caused by alterations in mitochondrial DNA (mtDNA) can lead to the initiation and progression of cancers and other diseases. These alterations include mutations and copy number variations. Especially, the mutations in D-loop, MT-ND1, and MT-ND5 affect mitochondrial functions and are widely detected in various cancers. Meanwhile, several other mutations have been correlated with muscular and neuronal diseases, especially MT-TL1 is deeply related. These pieces of evidence indicated mtDNA alterations in diseases show potential as a novel therapeutic target. mtDNA repair enzymes are the target for delaying or stalling the mtDNA damage-induced cancer progression and metastasis. Moreover, some mutations reveal a prognosis ability of the drug resistance. Current efforts aim to develop mitochondrial transplantation technique as a direct cure for deregulated mitochondria-associated diseases. This review summarizes the implications of mitochondrial dysfunction in cancers and other pathologies; and discusses the relevance of mitochondria-targeted therapies, along with their contribution as potential biomarkers.
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Affiliation(s)
- Ngoc Ngo Yen Nguyen
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea.,Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea
| | - Sung Soo Kim
- Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea.,Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Yong Hwa Jo
- Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea.,Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
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41
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Afkhami E, Heidari MM, Khatami M, Ghadamyari F, Dianatpour S. Detection of novel mitochondrial mutations in cytochrome C oxidase subunit 1 (COX1) in patients with familial adenomatous polyposis (FAP). Clin Transl Oncol 2019; 22:908-918. [PMID: 31552592 DOI: 10.1007/s12094-019-02208-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 09/13/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Familial adenomatous polyposis (FAP) is an Autosomal dominant inherited disorder and a rare form of colorectal cancer (CRC) that is characterized by the development of hundreds to thousands of adenomas in the rectum and colon. Mostly, cancers develop after the advent of the polyps. It appears in both sexes evenly, and the occurrence of the disease is in the second decade of life. Mitochondrial genome mutations have been reported with a variety of Tumors, but the precise role of these mutations in the pathogenicity and tumor progression is not exactly clear. Cytochrome c oxidase subunit I (COX1) is the terminal enzyme of the mitochondrial respiratory chain. The present study aims at assessing the occurrence of mtDNA mutations in COX1 gene in FAP patients and attempts to find out the cause and effect relationship between mitochondrial mutations and tumor progression. METHODS In this study, 56 FAP patients were investigated for the presence of the mutations in mitochondrial COX1 coding gene by PCR and sequencing analysis. All sequences that differed from the revised Cambridge Reference Sequence (rCRS) were classified as missense/ nonsense or silent mutations. Functional genomic studies using Bio-informatics tools were performed on the founded mutations to understand the downstream alterations in structure and function of protein. RESULTS We identified 38 changes in the COX1 gene in patients with FAP symptoms. Most of them were heteroplasmic changes of missense type (25/38). Tree of the changes (G6145A, C6988A, and T7306G) were nonsense mutations and had not been reported in the literature before. Our results of bioinformatics predictions showed that the identified mutations can affect mitochondrial functions, especially if the conservative domain of the protein is concerned. CONCLUSION Our findings indicate a high frequency of mtDNA mutations in all of the FAP cases compared to matched controls. These data significantly enhance our understanding of how such mutations contribute to cancer pathologies and develop the cancer treatment methods by new diagnostic biomarkers, and new drugs for gene therapy.
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Affiliation(s)
- E Afkhami
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
| | - M M Heidari
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.
| | - M Khatami
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
| | - F Ghadamyari
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
| | - S Dianatpour
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
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42
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Yusoff AAM, Abdullah WSW, Khair SZNM, Radzak SMA. A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies. Oncol Rev 2019; 13:409. [PMID: 31044027 PMCID: PMC6478002 DOI: 10.4081/oncol.2019.409] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 02/19/2019] [Indexed: 01/04/2023] Open
Abstract
Mitochondria are cellular machines essential for energy production. The biogenesis of mitochondria is a highly complex and it depends on the coordination of the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis. The most described mtDNA deletion in various human cancers is called the 4977-bp common deletion (mDNA4977) and it has been explored since two decades. In spite of that, its implication in carcinogenesis still unknown and its predictive and prognostic impact remains controversial. This review article provides an overview of some of the cellular and molecular mechanisms underlying mDNA4977 formation and a detailed summary about mDNA4977 reported in various types of cancers. The current knowledges of mDNA4977 as a prognostic and predictive marker are also discussed.
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Affiliation(s)
- Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Wan Salihah Wan Abdullah
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | | | - Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
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43
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Abstract
Thyroid cancers of follicular cell derivation provide excellent phenotype-genotype correlations. Current morphologic classifications are complex and require simplification. Benign adenomas have follicular or papillary architecture and bland cytology. Well-differentiated thyroid carcinomas exhibit follicular architecture, expansile growth, and variable cytologic atypia and invasiveness; low-risk tumors have excellent prognosis after surgical resection whereas widely-invasive and angioinvasive tumors warrant total thyroidectomy and radioablation. Papillary carcinoma is less differentiated; indolent microcarcinomas can be managed by active surveillance, whereas clinical lesions with local or distant spread require therapy. Progression gives rise to poorly differentiated and anaplastic carcinomas that are less common but far more aggressive.
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Affiliation(s)
- Sylvia L Asa
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
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44
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Abstract
Although differentiated thyroid carcinomas typically pursue an indolent clinical course, it is important to identify the subset of tumors that are most likely to behave aggressively so that patients with these tumors are counseled and treated appropriately. Extent of disease is fundamental to the prognostication for differentiated thyroid carcinoma; however, there are additional histologic features of the tumor separate from extent of disease that have been shown to affect clinical course. This review will start with a discussion of aggressive variants of papillary thyroid carcinoma, move to the prognostic significance of vascular invasion in follicular thyroid carcinoma, and finish with a discussion of Hürthle cell carcinoma, with an emphasis on why it is not considered a subtype of follicular thyroid carcinoma in the 2017 WHO Classification of Tumors of Endocrine Organs.
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Affiliation(s)
- Tyler Janovitz
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Justine A Barletta
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
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45
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Li W, Xia S, Aronova A, Min IM, Verma A, Scognamiglio T, Gray KD, Ullmann TM, Liang H, Moore MD, Elemento O, Zarnegar R, Fahey TJ. CHL1 expression differentiates Hürthle cell carcinoma from benign Hürthle cell nodules. J Surg Oncol 2018; 118:1042-1049. [PMID: 30311656 DOI: 10.1002/jso.25214] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/12/2018] [Accepted: 07/30/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Hürthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid cancer. Currently, cytologic analysis of fine-needle aspiration biopsy is limited in distinguishing benign Hürthle cell neoplasms from malignant ones. The aim of this study was to determine whether differences in the expression of specific genes could differentiate HCC from benign Hürthle cell nodules by evaluating differential gene expression in Hürthle cell disease. METHODS Eighteen benign Hürthle cell nodules and seven HCC samples were analyzed by whole-transcriptome sequencing. Bioinformatics analysis was carried out to identify candidate differentially expressed genes. Expression of these candidate genes was re-examined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was quantified by immunohistochemistry. RESULTS Close homolog of L1 (CHL1) was identified as overexpressed in HCC. CHL1 was found to have greater than 15-fold higher expression in fragments per kilobase million in HCC compared with benign Hurthle cell tumors. This was confirmed by qRT-PCR. Moreover, the immunoreactivity score of the CHL1 protein was significantly higher in HCC compared with benign Hürthle cell nodules. CONCLUSIONS CHL1 expression may represent a novel and useful prognostic biomarker to distinguish HCC from benign Hürthle cell disease.
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Affiliation(s)
- Wei Li
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Shujun Xia
- Ultrasound Department, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Anna Aronova
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Irene M Min
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Akanksha Verma
- Department of Physiology and Biophysics, Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York
| | - Theresa Scognamiglio
- Department of Pathology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Katherine D Gray
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Timothy M Ullmann
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Heng Liang
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Maureen D Moore
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York
| | - Rasa Zarnegar
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
| | - Thomas J Fahey
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York
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46
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Zhu Y, Dean AE, Horikoshi N, Heer C, Spitz DR, Gius D. Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy. J Clin Invest 2018; 128:3682-3691. [PMID: 30168803 DOI: 10.1172/jci120844] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Mammalian cells use a complex network of redox-dependent processes necessary to maintain cellular integrity during oxidative metabolism, as well as to protect against and/or adapt to stress. The disruption of these redox-dependent processes, including those in the mitochondria, creates a cellular environment permissive for progression to a malignant phenotype and the development of resistance to commonly used anticancer agents. An extension of this paradigm is that when these mitochondrial functions are altered by the events leading to transformation and ensuing downstream metabolic processes, they can be used as molecular biomarkers or targets in the development of new therapeutic interventions to selectively kill and/or sensitize cancer versus normal cells. In this Review we propose that mitochondrial oxidative metabolism is altered in tumor cells, and the central theme of this dysregulation is electron transport chain activity, folate metabolism, NADH/NADPH metabolism, thiol-mediated detoxification pathways, and redox-active metal ion metabolism. It is proposed that specific subgroups of human malignancies display distinct mitochondrial transformative and/or tumor signatures that may benefit from agents that target these pathways.
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Affiliation(s)
- Yueming Zhu
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Angela Elizabeth Dean
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Nobuo Horikoshi
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Collin Heer
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Douglas R Spitz
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - David Gius
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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47
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Masserrat A, Sharifpanah F, Akbari L, Tonekaboni SH, Karimzadeh P, Asharafi MR, Mazouei S, Sauer H, Houshmand M. Mitochondrial G8292A and C8794T mutations in patients with Niemann-Pick disease type C. Biomed Rep 2018; 9:65-73. [PMID: 29930807 PMCID: PMC6007046 DOI: 10.3892/br.2018.1095] [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: 11/02/2017] [Accepted: 04/27/2018] [Indexed: 11/06/2022] Open
Abstract
Niemann-Pick disease type C (NP-C) is a neurovisceral lipid storage disorder. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. NP-C is transmitted in an autosomal recessive manner and is caused by mutations in either the NPC1 (95% of families) or NPC2 gene. The estimated disease incidence is 1 in 120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. Variants of adenosine triphosphatase (ATPase) subunit 6 and ATPase subunit 8 (ATPase6/8) in mitochondrial DNA (mtDNA) have been reported in different types of genetic diseases including NP-C. In the present study, the blood samples of 22 Iranian patients with NP-C and 150 healthy subjects as a control group were analyzed. The DNA of the blood samples was extracted by the salting out method and analyzed for ATPase6/8 mutations using polymerase chain reaction sequencing. Sequence variations in mitochondrial genome samples were determined via the Mitomap database. Analysis of sequencing data confirmed the existence of 11 different single nucleotide polymorphisms (SNPs) in patients with NP-C1. One of the most prevalent polymorphisms was the A8860G variant, which was observed in both affected and non-affected groups and determined to have no significant association with NP-C incidence. Amongst the 11 polymorphisms, only one was identified in the ATPase8 gene, while 9 including A8860G were observed in the ATPase6 gene. Furthermore, two SNPs, G8292A and C8792A, located in the non-coding region of mtDNA and the ATPase6 gene, respectively, exhibited significantly higher prevalence rates in NP-C1 patients compared with the control group (P<0.01). The present study suggests that there may be an association between mitochondrial ATPase6/8 mutations and the incidence of NP-C disease. In addition, the mitochondrial SNPs identified maybe pathogenic mutations involved in the development and prevalence of NP-C. Furthermore, these results suggest a higher occurrence of mutations in ATPase6 than in ATPase8 in NP-C patients.
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Affiliation(s)
- Abbas Masserrat
- Department of Biology, Faculty of Science, Islamic Azad University, Damghan 3671639998, Iran
| | - Fatemeh Sharifpanah
- Department of Physiology, Faculty of Medicine, Justus Liebig University, D-35392 Giessen, Germany
| | - Leila Akbari
- Houshmand Genetic Diagnostics Laboratory, Taban Clinic, Tehran 1997844151, Iran
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia
| | - Seyed Hasan Tonekaboni
- Department of Neurology, Faculty of Medicine, Shahid Beheshti University, Tehran 19839-63113, Iran
| | - Parvaneh Karimzadeh
- Department of Neurology, Faculty of Medicine, Shahid Beheshti University, Tehran 19839-63113, Iran
| | - Mahmood Reza Asharafi
- Department of Neurology, Faculty of Medicine, Tehran University, Tehran 1417613151, Iran
| | - Safoura Mazouei
- Department of Cardiology, Clinic of Internal Medicine I, Friedrich Schiller University, D-07747 Jena, Germany
| | - Heinrich Sauer
- Department of Physiology, Faculty of Medicine, Justus Liebig University, D-35392 Giessen, Germany
| | - Massoud Houshmand
- Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161, Iran
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48
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Oncocytic Melanoma: A Study of a Rare Entity. Am J Dermatopathol 2018; 40:854-856. [PMID: 29771689 DOI: 10.1097/dad.0000000000001183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The authors report the second case of oncocytic melanoma, one of the rarest known melanoma variants. The diagnosis was established by Fontana stain positivity, expression of S100 protein as well as gp100/HMB45, and demonstration of numerous mitochondria by ultrastructure. Because it is known that some oncocytic tumors of the thyroid gland and kidney contain point mutations and common deletions of mitochondrial DNA, the complete mitochondrial DNA of the reported oncocytic melanoma was also studied. It was normal except for 2 private separate point mutations, predicted to be not pathogenic, which do not seem to play any role in the tumor phenotype.
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49
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Genomic and transcriptomic characterization of the mitochondrial-rich oncocytic phenotype on a thyroid carcinoma background. Mitochondrion 2018; 46:123-133. [PMID: 29631022 DOI: 10.1016/j.mito.2018.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 12/22/2022]
Abstract
We conducted the first systematic omics study of the oncocytic phenotype in 488 papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas. Oncocytic phenotype is secondary to PTC, being unrelated to several pathologic scores. The nuclear genome had low impact on this phenotype (except in specific copy number variation), which was mostly driven by the significant accumulation of mitochondrial DNA non-synonymous and frameshift mutations at high heteroplasmy levels. Energy and mitochondrial-related pathways were significantly enriched in oncocytic tumors that also displayed increased levels of expression for genes involved in autophagy and fusion of mitochondria. Our in vitro tests confirmed that autophagy is increased and functional while mitophagy is decreased in these tumors.
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50
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Acquaviva G, Visani M, Repaci A, Rhoden KJ, de Biase D, Pession A, Giovanni T. Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance. Histopathology 2018; 72:6-31. [PMID: 29239040 DOI: 10.1111/his.13380] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 08/28/2017] [Accepted: 08/29/2017] [Indexed: 02/05/2023]
Abstract
Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET-PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular-patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non-invasive follicular thyroid neoplasm with papillary-like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen-activated protein kinase and phosphoinositide 3-kinase-PTEN-AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance.
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Affiliation(s)
- Giorgia Acquaviva
- Anatomical Pathology, Molecular Diagnostic Unit, University of Bologna School of Medicine, Azienda USL di Bologna, Bologna, Italy
| | - Michela Visani
- Anatomical Pathology, Molecular Diagnostic Unit, University of Bologna School of Medicine, Azienda USL di Bologna, Bologna, Italy
| | - Andrea Repaci
- Endocrinology Unit, University of Bologna School of Medicine, Bologna, Italy
| | - Kerry J Rhoden
- Medical Genetics Unit, University of Bologna School of Medicine, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, Molecular Diagnostic Unit, University of Bologna, Azienda USL di Bologna, Bologna, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology, Molecular Diagnostic Unit, University of Bologna, Azienda USL di Bologna, Bologna, Italy
| | - Tallini Giovanni
- Anatomical Pathology, Molecular Diagnostic Unit, University of Bologna School of Medicine, Azienda USL di Bologna, Bologna, Italy
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