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Saadh MJ, Jasim NY, Ahmed MH, Ballal S, Kumar A, Atteri S, Vashishth R, Rizaev J, Alhili A, Jawad MJ, Yazdi F, Salajegheh A, Akhavan-Sigari R. Critical roles of miR-21 in promotions angiogenesis: friend or foe? Clin Exp Med 2025; 25:66. [PMID: 39998742 PMCID: PMC11861128 DOI: 10.1007/s10238-025-01600-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/11/2025] [Indexed: 02/27/2025]
Abstract
MiRNAs are small RNA strands that are managed following transcription and are of substantial importance in blood vessel formation. It is essential to oversee the growth, differentiation, death, movement and construction of tubes by angiogenesis-affiliated cells. If miRNAs are not correctly regulated in regard to angiogenesis, it can deteriorate the health and lead to various illnesses, which include cancer, cardiovascular disorder, critical limb ischemia, Crohn's disease, ocular diseases, diabetic microvascular complications, and more. Consequently, it is vital to understand the crucial part that miRNAs play in the development of blood vessels, so we can develop reliable treatment plans for vascular diseases. This write-up will assess the critical role of miR-21/exosomal miR-21 in managing angiogenesis associated with bone growth, wound recovery, and other pathological conditions like tumor growth, ocular illnesses, diabetes, and other diseases connected to formation of blood vessels. Previous investigations have demonstrated that miR-21 is present at higher amounts in certain cancerous cells, and it influences a multitude of genes that moderate the increased creation of blood vessels. Furthermore, studies demonstrated that exosomal miR-21 has the capacity to interact with endothelial cells to foster tumor angiogenesis. For that reason, this review explains the critical importance of miR-21/exosomal miR-21 in managing both healthy and diseased states of angiogenesis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Nisreen Yasir Jasim
- College of Nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | | | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhishek Kumar
- School of Pharmacy-Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Pharmacy, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Shikha Atteri
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjheri, Mohali, Punjab, 140307, India
| | - Raghav Vashishth
- Department of Surgery, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Jasur Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Farzaneh Yazdi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | | | - Reza Akhavan-Sigari
- Dr. Schneiderhan GmbH and ISAR Klinikum, Munich, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw, Management University Warsaw, Warsaw, Poland
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2
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Zhang S, Yang Y, Wang D, Yang X, Cai Y, Shui C, Yang R, Tian W, Li C. Exploring exosomes: novel diagnostic and therapeutic frontiers in thyroid cancer. Front Pharmacol 2024; 15:1431581. [PMID: 39584141 PMCID: PMC11581896 DOI: 10.3389/fphar.2024.1431581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 10/25/2024] [Indexed: 11/26/2024] Open
Abstract
In recent years, the incidence of thyroid cancer has surged globally, posing significant challenges in its diagnosis, treatment, and prognosis. Exosomes, as a class of extracellular vesicles, are secreted by nearly all cell types and encapsulate a variety of nucleic acids and proteins reflective of their cell of origin, thereby facilitating critical intercellular communication. Recent advancements in understanding these exosomes have catalyzed their application in oncology, particularly through uncovering their roles in the pathogenesis, diagnosis, and therapy of cancers. Notably, the latest literature highlights the integral role of exosomes in refining diagnostic techniques, enhancing targeted therapies, optimizing radiotherapy outcomes, and advancing immunotherapeutic approaches in thyroid cancer management. This review provides a current synthesis of the implications of exosomes in thyroid cancer tumorigenesis and progression, as well as their emerging applications in diagnosis and treatment strategies. Furthermore, we discuss the profound clinical potential of exosome-based interventions in managing thyroid cancer, serving as a foundational reference for future therapeutic developments.
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Affiliation(s)
- Sicheng Zhang
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yan Yang
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Dianri Wang
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xueting Yang
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yongcong Cai
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Chunyan Shui
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Ruoyi Yang
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
- Department of Oral and Maxillofacial Surgery, Guizhou Medical University, Guiyang, China
| | - Wen Tian
- Department of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Chao Li
- Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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3
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Perivoliotis K, Samara AA, Koutoukoglou P, Ntellas P, Dadouli K, Sotiriou S, Ioannou M, Tepetes K. Microvessel density in differentiated thyroid carcinoma: A systematic review and meta-analysis. World J Methodol 2022; 12:448-458. [PMID: 36186751 PMCID: PMC9516550 DOI: 10.5662/wjm.v12.i5.448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/30/2021] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Microvessel density (MVD) has been proposed as a direct quantification method of tumor neovascularization. However, the current literature regarding the role of MVD in differentiated thyroid carcinoma (DTC) remains inconclusive. AIM To appraise the effect of tumoral MVD on the survival of patients with DTC. METHODS This meta-analysis was based on the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The electronic databases Medline, Web of Science, and Scopus were systematically screened. A fixed-effects or random-effects model was used, according to the Cochran Q test. The data were then extracted and assessed on the basis of the Reference Citation Analysis (https://www.referencecitationanalysis.com/). RESULTS A total of nine studies were included in the present study. Superiority of low MVD tumors in terms of 10-year disease free survival (OR: 0.21, 95%CI: 0.08-0.53) was recorded. Lowly vascularized thyroid cancers had a lower recurrence rate (OR: 13.66, 95%CI: 3.03-61.48). Moreover, relapsing tumors [weighed mean difference (WMD): 11.92, 95%CI: 6.32-17.52] or malignancies with regional lymph node involvement (WMD: 8.53, 95%CI: 0.04-17.02) presented with higher tumoral MVD values. CONCLUSION MVD significantly correlates with the survival outcomes of thyroid cancer patients. However, considering several study limitations, further prospective studies of higher methodological and quality level are required.
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Affiliation(s)
| | - Athina A Samara
- Department of Surgery, University Hospital of Larissa, Larissa 41110, Greece
| | - Prodromos Koutoukoglou
- Postgraduate Programme Research Methodology in Biomedicine, Biostatistics and Clinical Bioinformatics, University of Thessaly, Larissa 41110, Greece
| | | | - Katerina Dadouli
- Postgraduate Programme Research Methodology in Biomedicine, Biostatistics and Clinical Bioinformatics, University of Thessaly, Larissa 41110, Greece
| | - Sotirios Sotiriou
- Department of Embryology, University of Thessaly, Larissa 41100, Greece
| | - Maria Ioannou
- Department of Pathology, University of Thessaly, Larissa 41100, Greece
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Kahn BM, Lucas A, Alur RG, Wengyn MD, Schwartz GW, Li J, Sun K, Maurer HC, Olive KP, Faryabi RB, Stanger BZ. The vascular landscape of human cancer. J Clin Invest 2021; 131:136655. [PMID: 33258803 DOI: 10.1172/jci136655] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypovascular tumors, enabling the classification of human tumors into 6 vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular "hub" genes. The EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Thus, we believe our studies provide an unbiased picture of human tumor vasculature that may enable more precise deployment of antiangiogenesis therapy.
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Affiliation(s)
- Benjamin M Kahn
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
| | - Alfredo Lucas
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
| | - Rohan G Alur
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
| | - Maximillian D Wengyn
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
| | - Gregory W Schwartz
- Abramson Family Cancer Research Institute.,Abramson Cancer Center.,Department of Pathology and Laboratory Medicine.,Penn Epigenetics Institute, and.,Department of Cancer Biology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jinyang Li
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
| | - Kathryn Sun
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
| | - H Carlo Maurer
- Department of Medicine, Division of Digestive Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA
| | - Kenneth P Olive
- Department of Medicine, Division of Digestive Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA
| | - Robert B Faryabi
- Abramson Family Cancer Research Institute.,Abramson Cancer Center.,Department of Pathology and Laboratory Medicine.,Penn Epigenetics Institute, and.,Department of Cancer Biology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ben Z Stanger
- Department of Medicine.,Department of Cell and Developmental Biology.,Abramson Family Cancer Research Institute.,Abramson Cancer Center
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5
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Jin Z, Zhu Y, Xie F, Zhang Y, Li N, Luo Y, Cao J. Contrast agent retention features in contrast-enhanced ultrasound: diagnostic performance for the prediction of papillary thyroid carcinoma. Clin Imaging 2021; 80:131-138. [PMID: 34315016 DOI: 10.1016/j.clinimag.2021.06.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 06/07/2021] [Accepted: 06/21/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE To report a new feature of contrast-enhanced ultrasound (CEUS) and its diagnostic performance for the prediction of papillary thyroid carcinoma (PTC). METHODS This retrospective study was conducted from October 2018 to March 2019, including 276 patients with 308 thyroid nodules who underwent CEUS examinations prior to surgery (90 patients, 122 nodules) or fine needle aspiration (186 patients, 186 nodules). Quantitative analysis of CEUS features was performed using time-intensity curves. After surgery, tissue sections stained with HE and an anti-CD34 primary antibody were used to characterize the cell number and microvessel density. The nodules were divided into retention and non-retention groups. RESULTS There were 168 malignant nodules and 140 benign nodules. The contrast-agent retention (CAR) feature was only observed in 52 papillary carcinomas. The CAR feature showed the sensitivity of 30.9% albeit the high specificity of 100%, for the diagnosis of thyroid cancers. The maximum slope coefficient of the washout index was significantly lower in the retention group than in the non-retention group (P < 0.001). The enhancement intensity during the late stage of enhancement index was significantly higher in the retention group than in the non-retention group (P < 0.001). The cell number and microvessel density in nodules with CAR features were higher (P < 0.001, P = 0.004). CONCLUSION The combination of the retention pattern of the CEUS observed herein with other CEUS features may be a useful tool to improve the diagnostic of the PTC.
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Affiliation(s)
- Zhuang Jin
- Department of Ultrasound, General hospital of Northern Theater Command, No.83, Wenhua Road, Shenhe District, Shenyang, Liaoning province 110018, China; Department of Ultrasound, First Medical Center of PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China
| | - Yaqiong Zhu
- Department of Ultrasound, First Medical Center of PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China
| | - Fang Xie
- Department of Ultrasound, First Medical Center of PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China
| | - Yan Zhang
- Department of Ultrasound, First Medical Center of PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China
| | - Nan Li
- Department of Ultrasound, First Medical Center of PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China
| | - Yukun Luo
- Department of Ultrasound, First Medical Center of PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China.
| | - Junying Cao
- Department of Ultrasound, General hospital of Northern Theater Command, No.83, Wenhua Road, Shenhe District, Shenyang, Liaoning province 110018, China.
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6
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Fu Z, Zhang J, Lu Y, Wang S, Mo X, He Y, Wang C, Chen H. Clinical Applications of Superb Microvascular Imaging in the Superficial Tissues and Organs: A Systematic Review. Acad Radiol 2021; 28:694-703. [PMID: 32418782 DOI: 10.1016/j.acra.2020.03.032] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/13/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022]
Abstract
Superb microvascular imaging (SMI) is an innovative Doppler technique for vascular examination. It uses an intelligent algorithm that efficiently separates low-speed flow signals from motion artifacts so that it can assess microvessels and the vessel distribution in detail. This article reviews the clinical applications of SMI in the disorders of superficial tissues and organs including thyroid nodules, breast tumors and lymph node diseases etc. More information of diseases that are closely associated with angiogenesis can be shown by SMI than other noninvasive examinations. Although some limitations exist, this safe and convenient technique is becoming acceptable and would play a more important role in disease diagnosis and therapeutic responses evaluation.
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Feng K, Ma R, Zhang L, Li H, Tang Y, Du G, Niu D, Yin D. The Role of Exosomes in Thyroid Cancer and Their Potential Clinical Application. Front Oncol 2020; 10:596132. [PMID: 33335859 PMCID: PMC7736410 DOI: 10.3389/fonc.2020.596132] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022] Open
Abstract
The incidence of thyroid cancer (TC) is rapidly increasing worldwide. The diagnostic accuracy and dynamics of TC need to be improved, and traditional treatments are not effective enough for patients with poorly differentiated thyroid cancer. Exosomes are membrane vesicles secreted specifically by various cells and are involved in intercellular communication. Recent studies have shown that exosomes secreted by TC cells contribute to tumor progression, angiogenesis and metastasis. Exosomes in liquid biopsies can reflect the overall molecular information of tumors, and have natural advantages in diagnosing TC. Exosomes also play an important role in tumor therapy due to their special physicochemical properties. TC patients will benefit as more exosome patterns are discovered. In this review, we discuss the role of TC-derived exosomes in tumorigenesis and development, and describe the application of exosomes in the diagnosis and treatment of TC.
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Affiliation(s)
- Kaixiang Feng
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Runsheng Ma
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lele Zhang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China
| | - Hongqiang Li
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China
| | - Yifeng Tang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China
| | - Gongbo Du
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Dongpeng Niu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Detao Yin
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Thyroid Surgery, Key Discipline Laboratory of Clinical Medicine of Henan, Zhengzhou, China
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Haytaoglu G, Kuzu F, Arpaci D, Altas A, Can M, Barut F, Kokturk F, Ilikhan SU, Bayraktaroglu T. Correlation of vascular endothelial growth factor and vascular endothelial growth factor receptor-1 levels in serum and thyroid nodules with histopathological and radiological variables. J Lab Physicians 2020; 11:51-57. [PMID: 30983803 PMCID: PMC6437829 DOI: 10.4103/jlp.jlp_41_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND/AIM: Vascular endothelial growth factor (VEGF) is a major cytokine in angiogenesis and has a role on aggressivity of various tumors. The expression of VEGF has been shown to increase in differential thyroid cancer. The aim of the study was to evaluate serum and intranodular VEGF (nVEGF) and VEGF receptor-1 (VEGFR-1) levels in patients with thyroid nodules and their relevance to ultrasonographic and pathological results. MATERIALS AND METHODS: A total of eighty patients were included in the study. Thyroid fine-needle aspiration biopsies were performed, and the levels of serum and nVEGF and VEGFR-1 were measured. Any possible correlations between serum and nVEGF, VEGFR-1, and biochemical/radiological variables were investigated. RESULTS: There were no significant differences between serum VEGF (sVEGF), nVEGF, sVEGFR-1, nVEGFR-1 levels, number of nodules, size of nodules, and benign and malignant ultrasonographic features. sVEGF and nVEGF were higher in malignant or suspicious nodules than that in benign nodules, but did not reach statistical significance (P > 0.05). sVEGFR-1 and nVEGFR-1 levels were higher in hyperthyroid patients than that in euthyroid patients (P < 0.05 and P = 0.003, respectively). nVEGFR-1 level was higher in hypothyroid patients than that in euthyroid patients (P = 0.016). sVEGF level was found to be higher in hyperactive nodules than that in others. Both sVEGFR-1 (P = 0.008) and nVEGF levels (P = 0.01) significantly increased with increasing age. nVEGFR-1 decreased with increasing body mass index (BMI) (P = 0.004). CONCLUSIONS: Our study showed the relationships of sVEGF, nVEGF, sVEGFR-1, and nVEGFR-1 levels with age, gender, BMI, and hyperthyroidism. To determine the role of VEGF/VEGFR-1 in thyroid nodules, further studies are required with a large number of patients.
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Affiliation(s)
- Gurkan Haytaoglu
- Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Fatih Kuzu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Evliya Çelebi Training and Research Hospital, Dumlupinar University, Kütahya, Turkey
| | - Dilek Arpaci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Ayfer Altas
- Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Murat Can
- Department of Biochemistry, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Figen Barut
- Department of Pathology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Furuzan Kokturk
- Department of Biostatistics, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Sevil Uygun Ilikhan
- Department of Internal Medicine, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Taner Bayraktaroglu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
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Jiang ZZ, Huang YH, Shen HL, Liu XT. Clinical Applications of Superb Microvascular Imaging in the Liver, Breast, Thyroid, Skeletal Muscle, and Carotid Plaques. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2019; 38:2811-2820. [PMID: 30953387 DOI: 10.1002/jum.15008] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 06/09/2023]
Abstract
This article reviews the clinical applications of Superb Microvascular Imaging (SMI; Canon Medical Systems, Otawara, Japan) in the liver, breast, thyroid, skeletal muscle, and carotid plaques. Diseases that are closely associated with angiogenesis can be diagnosed by SMI in a relatively early phase, and using SMI can prevent adverse reactions associated with the contrast agents used in contrast-enhanced ultrasound. Super Microvascular Imaging also shows particular value in grading disease activities and monitoring therapeutic responses. Although SMI has some limitations, such as a lack of clinical standards, it can add information to conventional ultrasound examinations and may become a noninvasive alternative to invasive diagnostic procedures for many clinical conditions.
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Affiliation(s)
- Zhen-Zhen Jiang
- Department of Ultrasound, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Yan-Hua Huang
- Department of Ultrasound, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Hua-Liang Shen
- Department of Ultrasound, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Xia-Tian Liu
- Department of Ultrasound, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
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10
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Wu F, Li F, Lin X, Xu F, Cui RR, Zhong JY, Zhu T, Shan SK, Liao XB, Yuan LQ, Mo ZH. Exosomes increased angiogenesis in papillary thyroid cancer microenvironment. Endocr Relat Cancer 2019; 26:525-538. [PMID: 30870812 DOI: 10.1530/erc-19-0008] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/14/2019] [Indexed: 12/22/2022]
Abstract
Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.
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MESH Headings
- Animals
- Biomarkers, Tumor/blood
- Case-Control Studies
- Cell Proliferation
- Collagen Type IV/blood
- Exosomes/metabolism
- Extracellular Matrix Proteins/blood
- Gene Expression Regulation, Neoplastic
- Human Umbilical Vein Endothelial Cells/metabolism
- Human Umbilical Vein Endothelial Cells/pathology
- Humans
- Hypoxia
- Male
- Mice
- Mice, Inbred BALB C
- MicroRNAs/blood
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Prognosis
- Thyroid Cancer, Papillary/blood supply
- Thyroid Cancer, Papillary/genetics
- Thyroid Cancer, Papillary/metabolism
- Thyroid Cancer, Papillary/pathology
- Thyroid Neoplasms/blood supply
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/metabolism
- Thyroid Neoplasms/pathology
- Transforming Growth Factor beta/blood
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Feng Wu
- Department of Endocrinology, The Third Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Department of Pathology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Fuxingzi Li
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiao Lin
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Feng Xu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Rong-Rong Cui
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jia-Yu Zhong
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ting Zhu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Su-Kang Shan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiao-Bo Liao
- Department of Cardiovascular Surgery, the Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ling-Qing Yuan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Zhao-Hui Mo
- Department of Endocrinology, The Third Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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Tasoulas J, Tsourouflis G, Theocharis S. Neovascularization: an attractive but tricky target in thyroid cancer. Expert Opin Ther Targets 2018; 22:799-810. [DOI: 10.1080/14728222.2018.1513494] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Jason Tasoulas
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gerasimos Tsourouflis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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12
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Recent Advances in the Classification of Low-grade Papillary-like Thyroid Neoplasms and Aggressive Papillary Thyroid Carcinomas: Evolution of Diagnostic Criteria. Adv Anat Pathol 2018; 25:263-272. [PMID: 29762157 DOI: 10.1097/pap.0000000000000198] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Papillary thyroid carcinomas account for ∼80% of well-differentiated thyroid tumors. During the past decade, several new variants of papillary-like thyroid neoplasms and papillary thyroid carcinomas have been recognized. Some of these neoplasms that were previously classified as malignant have been reclassified as low-grade neoplasms, as the diagnostic criteria have evolved. Similarly, some of the papillary thyroid carcinomas that were previously classified as conventional or classic papillary thyroid carcinomas have now been recognized as more aggressive variants of papillary thyroid carcinomas. Recognizing these differences becomes more important for the proper medical, surgical, and radiotherapeutic management of patients with these neoplasms.
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Ravaud A, de la Fouchardière C, Caron P, Doussau A, Do Cao C, Asselineau J, Rodien P, Pouessel D, Nicolli-Sire P, Klein M, Bournaud-Salinas C, Wemeau JL, Gimbert A, Picat MQ, Pedenon D, Digue L, Daste A, Catargi B, Delord JP. A multicenter phase II study of sunitinib in patients with locally advanced or metastatic differentiated, anaplastic or medullary thyroid carcinomas: mature data from the THYSU study. Eur J Cancer 2017; 76:110-117. [PMID: 28301826 DOI: 10.1016/j.ejca.2017.01.029] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 01/18/2017] [Accepted: 01/28/2017] [Indexed: 01/13/2023]
Abstract
PURPOSE Patients with advanced radioactive iodine resistant differentiated (MDTC) or medullary (MMTC) thyroid cancer had an unmet need. Early data showed promising efficacy of vascular endothelial growth factor receptor inhibitors. We investigated sunitinib in this setting. PATIENTS AND METHODS This phase 2 trial enrolled MDTC, anaplastic (MATC) and MMTC patients in 1st line anti-angiogenic therapy with sunitinib at 50 mg/d, 4/6w. Objective response rate was the primary end-point. Secondary end-points were progression-free survival, overall survival and safety. RESULTS Seventy-one patients were enrolled from August 2007 to October 2009, 41 MDTC/4 MATC patients and 26 MMTC patients. Patients received a median of 8 and 9 cycles, respectively. In the MDTC/MATC group, 13% of patients and 43% of cycles and in the MMTC group, 23% of the patients and 48.8% of cycles remained at 50 mg/d, respectively. The primary end-point was reached with an objective response rate of 22% (95% CI: 10.6-37.6) in MDTC patients and in 38.5% (95% CI: 22.6-56.4) in MMTC patients. No objective response was seen in MATC patients. Median progression-free survival and overall survival were 13.1 and 26.4 months in MDTC patients, 16.5 and 29.4 months in MMTC patients. The most frequent side effects were asthenia/fatigue (27.8% ≥ grade 3), mucosal (9.9% ≥ grade 3), cutaneous toxicities, hand-foot syndrome (18.3% ≥ grade 3). Of all, 14.1% had a cardiac event. Nine unexpected side effects were reported, out of which, five induced deaths. CONCLUSION Sunitinib is active in MDTC and MMTC patients. Side effects were more severe than with previous reports. If using sunitinib, alternative schedule/dosage should be considered.
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MESH Headings
- Adenocarcinoma, Follicular/drug therapy
- Adenocarcinoma, Follicular/secondary
- Adult
- Aged
- Angiogenesis Inhibitors/therapeutic use
- Bone Neoplasms/drug therapy
- Bone Neoplasms/secondary
- Carcinoma/drug therapy
- Carcinoma/pathology
- Carcinoma/secondary
- Carcinoma, Neuroendocrine/drug therapy
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Neuroendocrine/secondary
- Carcinoma, Papillary
- Female
- Humans
- Indoles/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/secondary
- Lung Neoplasms/drug therapy
- Lung Neoplasms/secondary
- Lymph Nodes/pathology
- Lymphatic Metastasis
- Male
- Middle Aged
- Neck
- Pyrroles/therapeutic use
- Sunitinib
- Thyroid Cancer, Papillary
- Thyroid Carcinoma, Anaplastic/drug therapy
- Thyroid Carcinoma, Anaplastic/pathology
- Thyroid Carcinoma, Anaplastic/secondary
- Thyroid Neoplasms/drug therapy
- Thyroid Neoplasms/pathology
- Thyroid Neoplasms/secondary
- Treatment Outcome
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Affiliation(s)
- Alain Ravaud
- Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; Clinical Investigational Center, CIC. INSERM CIC 1401, Bordeaux University Hospital, Bordeaux, France; Bordeaux University, Bordeaux, France.
| | | | - Philippe Caron
- Department of Endocrinology, Toulouse University Hospital, Toulouse, France
| | - Adelaïde Doussau
- Methodology Research Unit, Bordeaux University Hospital, Bordeaux, France
| | - Christine Do Cao
- Department of Endocrinology, Lille University Hospital, Lille, France
| | - Julien Asselineau
- Methodology Research Unit, Bordeaux University Hospital, Bordeaux, France
| | - Patrice Rodien
- Department of Endocrinology, Angers University Hospital, Angers, France
| | - Damien Pouessel
- Department of Medical Oncology, Cancer Institute of Montpellier, Montpellier, France
| | | | - Marc Klein
- Department of Endocrinology, Nancy University Hospital, Nancy, France
| | | | - Jean-Louis Wemeau
- Department of Endocrinology, Lille University Hospital, Lille, France
| | - Anne Gimbert
- Pharmacovigilance Unit, Bordeaux University Hospital, Bordeaux, France
| | | | - Delphine Pedenon
- Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France
| | - Laurence Digue
- Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France
| | - Amaury Daste
- Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; Bordeaux University, Bordeaux, France
| | - Bogdan Catargi
- Department of Endocrinology, Bordeaux University Hospital, Bordeaux, France
| | - Jean-Pierre Delord
- Department of Medical Oncology, Institut Claudius Régaud, IUCT, Toulouse, France
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Bingül İ, Vural P, Doğru-Abbasoğlu S, Çil E, Uysal M. Vascular endothelial growth factor G+405C polymorphism may contribute to the risk of developing papillary thyroid carcinoma. J Clin Lab Anal 2016; 31. [PMID: 27925342 DOI: 10.1002/jcla.22110] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 11/10/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Vascular endothelial growth factor (VEGF) is a mediator implicated with cell proliferation, differentiation and migration, and monocyte/macrophage chemotaxis. In present study, we aimed to investigate the relationship between VEGF gene polymorphisms (G+405C, T-460C, and A-2578C) and PTC susceptibility. METHODS DNA was isolated from peripheral blood leukocytes of 127 patients with PTC and 203 healthy controls. Genotyping was performed by real-time PCR. Association of genotypes with susceptibility of PTC was analyzed with multivariate logistic regression adjusted for age, gender and smoking status. RESULTS AND CONCLUSION In G+405C polymorphism, the frequencies of C allele (related with increased VEGF production) and combined CG+CC genotype were found to be higher (3.5 and 5-fold, respectively) among patients with PTC than controls (P<.001). However, VEGF T-460C and A-2578C polymorphisms are not associated with PTC risk. There was no relationship between VEGF polymorphisms and clinical/laboratory parameters of PTC. Haplotype analysis demonstrated that there was a strong linkage disequilibrium (LD) between -460/-2578 (D'=.89, r2 =.79), weak LD between +405/-460 (D'=.422, r2 =.035), and +405/-2578 (D'=.43, r2 =.038) locuses. Additionally, the +405/-460/-2578 GTA haplotype was found to be protective, whereas CTA haplotype to be related with increased PTC risk. As a conclusion, we suggest that VEGF G+405C polymorphism is associated with increased risk of PTC.
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Affiliation(s)
- İlknur Bingül
- Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul University, Istanbul, Turkey
| | - Pervin Vural
- Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul University, Istanbul, Turkey
| | - Semra Doğru-Abbasoğlu
- Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul University, Istanbul, Turkey
| | - Esra Çil
- II. Internal Medicine Clinic, Department of Endocrinology, Şişli Etfal Education and Research Hospital, Istanbul, Turkey
| | - Müjdat Uysal
- Istanbul Faculty of Medicine, Department of Biochemistry, Istanbul University, Istanbul, Turkey
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Krátký J, Vítková H, Bartáková J, Telička Z, Antošová M, Límanová Z, Jiskra J. Thyroid nodules: pathophysiological insight on oncogenesis and novel diagnostic techniques. Physiol Res 2015; 63 Suppl 2:S263-75. [PMID: 24908232 DOI: 10.33549/physiolres.932818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Thyroid nodules are a very frequent pathology among common population. Despite the vast majority of them are of benign origin, the incidence of thyroid cancer is currently rather rising. Although there are several risk factors of thyroid cancer and several clinical, ultrasound, biochemical and molecular diagnostic markers, the exact mechanisms of thyroid oncogenesis and the linkage between thyroid nodule ultrasound appearance and its biological character remain unclear. While ionizing radiation is the only one well-known risk factor for thyroid cancer, the significance of some others remains unclear. The aim of our review was to discuss some not completely known pathophysiological mechanisms involved in thyroid oncogenesis as hypothyroidism, mutations of genes regulating cell proliferation, thyroid autoimmunity and pregnancy and to describe pathophysiological background of some ultrasound markers of thyroid cancer (size, echogenicity, vascularization, calcifications and stiffness). Better knowledge in this field is crucial for development of novel diagnostic techniques and therapeutic approaches. For example, the analysis of BRAF, RAS and other mutations in cytological samples may help to distinction between follicular thyroid carcinoma and follicular thyroid adenoma and may significantly decrease the number of unnecessary surgery among patients with thyroid nodules. Alternatively, the different malign cells growth, angiogenesis, destructions of thyroid follicles, reparative changes, growth retardation, fibrosis and increased interstitial fluid pressure implicate the typical ultrasound appearance of papillary thyroid cancer (hypoechogenicity, irregular vascularization, microcalcifications, stiffness) which is essential to catch the suspicious nodules on the basis of their ultrasound appearance among large amount of benign nodules.
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Affiliation(s)
- J Krátký
- Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
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16
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Gulubova M, Ivanova K, Ananiev J, Gerenova J, Zdraveski A, Stoyanov H, Vlaykova T. VEGF expression, microvessel density and dendritic cell decrease in thyroid cancer. BIOTECHNOL BIOTEC EQ 2014; 28:508-517. [PMID: 26019537 PMCID: PMC4433839 DOI: 10.1080/13102818.2014.909151] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 11/26/2013] [Indexed: 12/14/2022] Open
Abstract
Thyroid cancer is one of the five most common cancers in the age between 20 and 50 years. Many factors including the potent angiogenic vascular endothelial growth factor (VEGF) and different dendritic cell types are known to be related to thyroid tumourogenesis. The study was performed to address the expression of VEGF and microvessel density in thyroid cancers and to evaluate the effect of VEGF expression in thyroid tumour cells on the dendritic cells. We investigated 65 patients with different types of thyroid carcinomas: papillary (PTC), oncocytic (OTC), follicular (FTC) and anaplastic (ATC), immunohistochemically with antibodies against VEGF, CD1a, CD83, S100 and CD31. Our results suggest that the expression of VEGF is significantly more often in PTC than ATC (92.3% vs. 60.0%, p = 0.025). The microvessel density marked with CD31 in the tumour border of PTC was significantly higher as compared to FTC (p = 0.039), but not to ATC and OTC (p = 0.337 and 0.134). We found that CD1a- and CD83-positive cells were dispersed with variable density and in OC CD31+ vessel numbers were positively correlated with CD83+ dendritic cells in tumour stroma (R = 0.847, p = 0.016). We did not find statistically significant associations of the survival of patients with PTC after the surgical therapy with VEGF expression and MVD. In conclusion we may state that VEGF expression in tumour cells of thyroid cancer can induce neovascularization and suppress dendritic cells.
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Affiliation(s)
- Maya Gulubova
- Department of General and Clinical Pathology, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
| | - Koni Ivanova
- Department of General and Clinical Pathology, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
| | - Julian Ananiev
- Department of General and Clinical Pathology, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
| | - Julieta Gerenova
- Department of Endocrinology, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
| | - Aleksandar Zdraveski
- Department of General Surgery, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
| | - Hristo Stoyanov
- Department of General Surgery, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
| | - Tatyana Vlaykova
- Department of Chemistry and Biochemistry, Medical Faculty, Trakia University , Stara Zagora , Bulgaria
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17
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Relationships between Lymph Node Metastasis and Expression of CD31, D2-40, and Vascular Endothelial Growth Factors A and C in Papillary Thyroid Cancer. Clin Exp Otorhinolaryngol 2012; 5:150-5. [PMID: 22977712 PMCID: PMC3437416 DOI: 10.3342/ceo.2012.5.3.150] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 01/11/2012] [Accepted: 02/02/2012] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVES To investigate the relationships between lymph node metastasis (LNM) and expression of CD31, D2-40 and vascular endothelial growth factors (VEGF)-A and -C in patients with papillary thyroid cancer (PTC). METHODS Paraffin-embedded thyroid tissues of 72 patients were evaluated, which included 25 patients with thyroid nodular hyperplasia (TNH), 24 PTC patients without LNM, and 23 PTC patients with LNM. Three pathologists, who were blinded to the patient's clinical information, assessed the immunohistochemical staining results. The amount of expression was scored as high (>25% of cells stained) or low (0-25%). RESULTS A higher level of VEGF-A expression was observed in the PTC groups regardless of LNM when compared to the group with TNH (91.3%, 79.2%, 4.0%, respectively). VEGF-C expression in the PTC with LNM group was significantly higher than the other two groups (P<0.05). No difference in microvessel density (MVD) scores was observed using CD31 among the three groups. The lymphatic vessel density (LVD) score using D2-40 was significantly higher in patients having PTC with LNM than the other groups (P<0.05). CONCLUSION VEGF-C and D2-40 were more highly expressed in patients having PTC with LNM than in patients having PTC without LNM or in those having TNH. Analysis of VEGF-C level and LVD using D2-40 may be helpful in the diagnosis of PTC and the evaluation of LNM potential in patients with PTC.
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18
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Lewy GD, Sharma N, Seed RI, Smith VE, Boelaert K, McCabe CJ. The pituitary tumor transforming gene in thyroid cancer. J Endocrinol Invest 2012; 35:425-33. [PMID: 22522436 DOI: 10.3275/8332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The pituitary tumor transforming gene (PTTG) is a multifunctional proto-oncogene that is over-expressed in various tumors including thyroid carcinomas, where it is a prognostic indicator of tumor recurrence. PTTG has potent transforming capabilities in vitro and in vivo, and many studies have investigated the potential mechanisms by which PTTG contributes to tumorigenesis. As the human securin, PTTG is involved in critical mechanisms of cell cycle regulation, whereby aberrant expression induces aneuploidy. PTTG may further contribute to tumorigenesis through its role in DNA damage response pathways and via complex interactions with hormones and growth factors. Furthermore, PTTG over-expression negatively impacts upon the efficacy of radioiodine therapy in thyroid cancer, through repression of expression and function of the sodium iodide symporter. Given its various roles at all disease stages, PTTG appears to be an important oncogene in thyroid cancer. This review discusses the current knowledge of PTTG with particular focus on its role in thyroid cancer.
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Affiliation(s)
- G D Lewy
- School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
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19
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Intratumoural lymph vessel density is related to presence of lymph node metastases and separates encapsulated from infiltrative papillary thyroid carcinoma. Virchows Arch 2011; 459:595-605. [DOI: 10.1007/s00428-011-1161-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Revised: 10/18/2011] [Accepted: 10/19/2011] [Indexed: 01/04/2023]
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Abstract
The histology and clinical behavior of thyroid cancer are highly diverse. Although most are indolent tumors with a very favorable outcome with the current standard of care therapy, a small subset of tumors may be among the most lethal malignancies known to man. While surgery and radioactive iodine are the standard of care for differentiated thyroid cancers (DTC) and are effective in curing a majority of such patients, those with iodine-resistant cancers pose a great challenge for clinicians, as these patients have limited treatment options and poor prognoses. Medullary thyroid carcinoma (MTC) has no effective systemic therapy despite the genetic and signaling defects that have been well characterized for the last two decades. Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors that remains fatal despite conventional multimodality therapy. Increased understanding of the pathogenesis of papillary thyroid carcinoma, the most common type of DTC, as well as ATC, has led to the development of targeted therapies aimed at signaling pathways and angiogenesis that are critical to the development and/or progression of such tumors. Development of tyrosine kinase inhibitors targeting known pathogenetic defects in MTC has led to testing of such agents in the clinic. Numerous clinical trials have been conducted over the last 5 years to examine the effects of these targeted molecular therapies on the outcomes of patients with iodine-refractory DTC, MTC and ATC. Conduction of such trials in the last few years represents a major breakthrough in the field of thyroid cancer. Several trials testing targeted therapies offer promise for setting new standards for the future of patients with progressive thyroid cancer. The purpose of this paper is to outline the recent advances in understanding of the pathogenesis of thyroid cancer and to summarize the results of the clinical trials with these targeted therapies.
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Affiliation(s)
- Jennifer A Sipos
- Division of Endocrinology, The Ohio State University, Columbus, OH, USA
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TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene 2011; 30:3011-23. [PMID: 21339735 DOI: 10.1038/onc.2011.18] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.
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Abstract
It is well known that radiation significantly impacts the morbidity of thyroid cancer and that is why Belarus has the highest incidence of the malignancy. Author describes statistical data, classification of angiogenesis, and typical pathological features of malignant thyroid diseases with regard to the vascular network.
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Affiliation(s)
- Matvey Vladimir Sprindzuk
- United Institute of Informatics Problems, National Academy of Sciences of Belarus, Minsk. Belarus, 220040, Minsk, Bogdanovicha lane, 112/38. ,
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Hsueh C, Lin JD, Wu IC, Chao TC, Yu JS, Liou MJ, Yeh CJ. Vascular endothelial growth factors and angiopoietins in presentations and prognosis of papillary thyroid carcinoma. J Surg Oncol 2010; 103:395-9. [PMID: 21400522 DOI: 10.1002/jso.21844] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Accepted: 11/29/2010] [Indexed: 01/27/2023]
Abstract
AIMS Angiogenesis from thyroid cancer cell plays the important roles in post-surgical persistent, recurrent, and metastatic papillary thyroid cancer (PTC). This study is to investigate the expression of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), Tek/Tie-2 receptor, and vascular endothelial growth factors (VEGF) in normal, benign thyroid tissues and different stage of PTC. We expect angiogenetic factors are important in the presentation of local-regional neck or distant metastases in PTC. MATERIALS AND RESULTS A total of 101 tissues from the subjects underwent thyroidectomy were enrolled in the study. There were 22 control and 79 thyroid cancer patients in different TNM stagings were collected. Ang-1 illustrated highest mean immunostaining score in metastatic group. Comparing with normal and benign thyroid tissues, thyroid cancer tissues illustrated significantly high expression of three angiogenetic factors and Tie-2 receptor. Of the PTC, significantly high expression of three angiogenetic factors and Tie-2 receptor were illustrated in recurrent cases. VEGF showed statistical difference in disease-free cancer mortality, and recurrent groups. CONCLUSIONS Immunochemical staining illustrated VEGF, Ang-1, Ang-2 expression in PTC tissues related to clinical staging; however, we need more information concerning these factors with long-term follow-up results.
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Affiliation(s)
- Chuen Hsueh
- Department of Pathology, Chang Gung Memorial Hospital, Linkou, Chang Gung University College of Medicine, Taiwan, R.O.C
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Capp C, Wajner SM, Siqueira DR, Brasil BA, Meurer L, Maia AL. Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid 2010; 20:863-71. [PMID: 20615131 DOI: 10.1089/thy.2009.0417] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF-A) expression is upregulated in the majority of human tumors, where it stimulates proliferation, migration, and survival of endothelial cells. Studies have suggested that VEGF inhibitors can be used as an alternative therapy in medullary thyroid carcinoma (MTC), but data about expression of VEGF-A and its receptor in this tumor are scarce. The aims of this study were to evaluate VEGF-A, VEGF receptor (VEGFR)-1, VEGFR-2, and microvessel density (MVD) expression in MTC samples and correlate it with clinical parameters. METHODS Paraffin-embedded samples from 38 MTC patients were evaluated for VEGF-A, VEGFR-1, VEGFR-2, and MVD expression by immunohistochemistry. Clinical data were retrospectively reviewed in medical records. RESULTS Thirty-eight patients aged 31.8 +/- 17.1 years were enrolled. Twenty-seven patients had hereditary disease (71.1%). Twenty-five of them were found to have multiple endocrine neoplasia (MEN) 2A and two were found to have MEN 2B. VEGF-A immunohistochemical staining was detected in 95% (36/38), VEGFR-1 in 96% (36/37), and VEGFR-2 in 91% (31/34) of MTC samples. Age at surgery was positively correlated with VEGFR-2 (p = 0.003). There was no correlation between VEGF-A, VEGFR-2, and tumor stage (tumor node metastasis). Nevertheless, VEGFR-1 was found to be inversely correlated with tumor node metastasis (p = 0.034). We also observed a trend toward an association between VEGFR-1 signal intensity and cure of disease, although this did not reach statistical significance (p = 0.054). Neither VEGF-A nor VEGFR-2 was associated with disease outcome after a median follow-up period of 5 years (p = 0.882 and p = 0.236, respectively). As expected, MVD was correlated with age at surgery (p = 0.005) and tumor size (p = 0.03). Patients with the hereditary form of the disease had a stronger intensity for VEGFR-1 (p = 0.039), whereas patients with sporadic disease displayed higher MVD counts (44 [27-63] vs. 21 [9-49], p = 0.018). CONCLUSION The VEGF-A, VEGFR-1, and VEGFR-2 immunoreactive proteins are overexpressed in MTC lesions and might be implicated in tumor progression. It is not clear, however, if expression of these molecules provides prognostic information regarding the spread or outcome of MTC.
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Affiliation(s)
- Clarissa Capp
- Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul , Porto Alegre, RS, Brazil
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Cheong H, Kang H, Kim HK, Bae JY, Song DE, Cho MS, Sung SH, Han WS, Koo H. Microvessel and Lymphatic Vessel Density and VEGFR-3 Expression of Papillary Thyroid Carcinoma with Comparative Analysis of Clinicopathological Characteristics. KOREAN JOURNAL OF PATHOLOGY 2010. [DOI: 10.4132/koreanjpathol.2010.44.3.243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Harin Cheong
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Hanna Kang
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Hyung Kyung Kim
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ji Yoon Bae
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Dong Eun Song
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Min Sun Cho
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sun Hee Sung
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Woon Sup Han
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Heasoo Koo
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
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de Araujo-Filho VJF, Alves VAF, de Castro IV, Lourenço SV, Cernea CR, Brandão LG, Ferraz AR. Vascular endothelial growth factor expression in invasive papillary thyroid carcinoma. Thyroid 2009; 19:1233-7. [PMID: 19888861 DOI: 10.1089/thy.2008.0179] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND The vascular endothelial growth factor (VEGF) is a major promoter of endothelial growth and migration. Some studies have shown a correlation between expression of this growth factor and prognosis in several cancers, including well-differentiated thyroid cancer. AIM We studied VEGF expression, local invasiveness, and other prognostic factors in papillary thyroid carcinoma (PTC) to test the hypothesis that the expression of VEGF is correlated with the degree of invasion of PTC. PATIENTS AND METHODS Clinical and pathological data of 76 patients with PTC were retrospectively reviewed. Group 1 consisted of patients with gross locally invasive tumors, group 2 consisted of patients with only invasion of the thyroid capsule, and group 3 consisted of patients with noninvasive PTC. RESULTS VEGF expression was noted within the tumor in all groups of PTC patients but was absent in the surrounding normal tissue. Older patients had higher expression of VEGF than younger patients. The age of patients with strong reaction to VEGF was 46 +/- 14 (mean +/- standard deviation), and that in patients with a weaker reaction was 39 +/- 16 (p < 0.05). Only 20% of patients with a follicular variant of PTC had a strong reaction to VEGF compared with 68% of patients with classical PTC (p < 0.01). CONCLUSIONS VEGF expression appears to be an early event in the development of PTC. Whether VEGF expression promotes the progression of PTC is not known, but the answer to this question may be important in view of its greater expression in older patients, a group whose prognosis in PTC is worse.
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Sercu S, Zhang L, Merregaert J. The extracellular matrix protein 1: its molecular interaction and implication in tumor progression. Cancer Invest 2008; 26:375-84. [PMID: 18443958 DOI: 10.1080/07357900701788148] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The extracellular matrix protein 1 (ECM1) is expressed around blood vessels, which suggest a role for ECM1 in angiogenesis. Recombinant ECM1 stimulates proliferation of cultured endothelial cells and promotes blood vessel formation in the chorioallantoic membrane of chicken embryos. These observations make ECM1 a possible trigger for angiogenesis, tumor progression and malignancies. Interaction of ECM1 with perlecan, MMP-9 and fibulin-1C/D contributes to this hypothesis. However, the importance of ECM1 in cancer biology has been neglected so far. Nevertheless, a survey of ECM1 expression in different tumors indicated that ECM1, although not tumor specific, is significantly elevated in many malignant epithelial tumors that give rise to metastases, emphasizing its relevance in the cancer process.
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Affiliation(s)
- S Sercu
- Laboratory of Molecular Biotechnology, Department of Biomedical Sciences, University of Antwerp, Belgium
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28
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Gautron L. [Gustave Roussy's (1874-1948) contribution to neuroendocrinology]. ANNALES D'ENDOCRINOLOGIE 2007; 68:400-402. [PMID: 17996213 DOI: 10.1016/j.ando.2007.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2007] [Revised: 09/26/2007] [Accepted: 09/27/2007] [Indexed: 05/25/2023]
Abstract
Gustave Roussy (1874-1948) is remembered as a distinguished French neuropathologist and a leader in the field of oncology. However, his original contribution to the study of hypothalamic functions and neuroendocrinology remains ignored. Among Roussy's discoveries is the first experimental demonstration of the hypothalamic origin of diabetes insipidus and adiposo-genital dystrophy. Also, based on his own histological work, he pioneered the concept of neurosecretion, which was termed by him "neuricrinie".
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Affiliation(s)
- L Gautron
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9077, USA.
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29
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VEGF in physiological process and thyroid disease. ANNALES D'ENDOCRINOLOGIE 2007; 68:438-48. [PMID: 17991452 DOI: 10.1016/j.ando.2007.09.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2007] [Revised: 09/26/2007] [Accepted: 09/27/2007] [Indexed: 01/04/2023]
Abstract
Angiogenesis is a physiological process involving the growth of new vessels from pre-existing vasculature. Vascular endothelial growth factor (VEGF) is an important regulator of both benign and malignant disease processes in the thyroid gland. The VEGF family includes seven members respectively named VEGF-A, also known as VPF (vascular permeability factor), VEGF-B, VEGF-C, VEGF-D, all described in mammals, VEGF-E (found in Parapoxviridae), VEGF-F (also called svVEGF, for snake venom VEGF, found in viper venom) and PlGF (placental growth factor). Thyrocytes are able to synthesize and secrete VEGF. VEGF-A is implicated in tumour growth and metastasis via blood vessels while VEGF-C and VEGF-D, involved in lymphangiogenesis, favour metastasis to the cervical lymph nodes in papillary thyroid carcinomas. High levels of VEGF expression in thyroid tumour cells may correlate with a poorer outcome in papillary thyroid carcinomas. Because of its important role in malignant angiogenesis, VEGF is the preferential target of a new variety of therapeutic agents called angiogenesis inhibitors.
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Jebreel A, England J, Bedford K, Murphy J, Karsai L, Atkin S. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathol 2007; 88:271-7. [PMID: 17696908 PMCID: PMC2517322 DOI: 10.1111/j.1365-2613.2007.00533.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Angiogenesis is critical for the growth and metastatic spread of tumours. Vascular endothelial growth factor (VEGF) is the most potent inducer of neovasculature, and its increased expression has been related to a worse clinical outcome in many diseases. The purpose of this study was to evaluate the relation between VEGF, its receptors (VEGFR-1 and VEGFR-2) and microvessel density (MVD) in thyroid diseases. Immunostaining for VEGF and VEGF receptors was performed in 66 specimens of thyroid tissue, comprising 17 multinodular goitre (MNG), 14 Graves' disease, 10 follicular adenoma, 8 Hashimoto's thyroiditis, 7 papillary carcinoma and 10 normal thyroid specimens. Thyrocyte positivity for VEGF and VEGF receptors was scored 0-3. Immunohistochemistry for CD31, and CD34 on the same sections was performed to evaluate MVD. Immunohistochemical staining of VEGF in thyrocytes was positive in 92% of all the thyroid tissues studied. Using an immunostaining intensity cut off of 2, increased thyrocyte staining was seen in follicular adenoma specimens, MNG and normal thyroids compared with Hashimoto's thyroiditis and Graves' disease (P < 0.05). Similarly, VEGF thyrocyte expression in Graves' disease was less than other pathologies (P < 0.05). VEGFR-1 expression and the average MVD score did not differ between the different thyroid pathologies. VEGF expression was lower in autoimmune pathologies compared to autonomous growth processes. Conversely, both VEGFR-1 and VEGFR-2 were widely expressed in benign and neoplastic thyroid disease, suggesting that the up-regulation of VEGF and not its receptors occurs as tissue becomes autonomous. There was no clear relationship between MVD measurement and thyroid pathology.
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31
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Larsen KK, Andersen NF, Melsen F, Sørensen FB. Vascularity in thyroid neoplasms: a methodological investigation with a view to diagnostics. APMIS 2006; 114:749-56. [PMID: 17078854 DOI: 10.1111/j.1600-0463.2006.apm_363.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The aim of the present study was to evaluate the reliability of four different methods (vascular grading, Chalkley count, microvessel density (MVD) and stereological estimation) for quantifying intratumoral microvascularity in thyroid neoplasms, by comparing the variability within and between observers. In addition, the diagnostic and prognostic potential of neovascularity expressed by the four methods was evaluated. The study had a retrospective design and involved 24 follicular adenomas (FA), 19 follicular carcinomas (FC), and 17 papillary carcinomas (PC). Chalkley count was reproducible both within and between observers. MVD was not reproducible. Within observer the reproducibility of vascular grading was substantial, between observers it was fair to moderate. Stereological estimation was a priori considered reproducible. Keeping time consumption, cost and reproducibility in mind, Chalkley count should be the preferred method for assessing microvascularity in thyroid neoplasms. The diagnostic evaluation revealed a tendency towards higher degree of vascularity in FA compared to both FC and PC for all methods. No statistically significant association was seen between vascular density and prognosis.
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32
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Romani AA, Borghetti AF, Del Rio P, Sianesi M, Soliani P. The risk of developing metastatic disease in colorectal cancer is related to CD105-positive vessel count. J Surg Oncol 2006; 93:446-55. [PMID: 16615157 DOI: 10.1002/jso.20456] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Angiogenesis is a complex multistep process that involves extracellular matrix remodeling, migration and proliferation of endothelial cells, and morphogenesis of microvessels. CD105 (endoglin), a co-receptor of the TGF-beta superfamily, was proposed as a marker of neovascularization in solid malignancies. The aim of this study was to evaluate retrospectively the effect of CD105-assessed angiogenesis on the risk of developing metastatic disease in colorectal cancer (CRC). METHODS One hundred and twenty-five paraffin-embedded samples were analyzed by immunohistochemical methods using a CD105 monoclonal antibody. The median follow-up was 70.8 months. Survivals were calculated from actuarial estimates, and logistic regression predicted the risk of developing metastatic disease. RESULTS The CD105-vessel count was strongly correlated with the occurrence of metastatic disease. The median CD105-positive vessels in patients with and without metastatic disease were 24.7 and 13.2 vessels/mm(2), respectively (P < 0.001). For each one microvessel increase in the vessels count per 400x field, there was a 1.42-fold increase in the risk of metastatic disease (P < 0.001). CONCLUSIONS The assessment of tumor angiogenesis with anti-CD105 was not sufficient for its use as a surrogate end point for survival because of the amount of survival variability explained was only 8% in absence of metastatic disease. In contrast, multivariate logistic regression analysis revealed that CD105-vessels count can identify patients at high risk of metastatic disease.
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Affiliation(s)
- Antonello A Romani
- Dipartimento di Medicina Sperimentale, Sezione di Patologia Molecolare ed Immunologia, Università degli Studi di Parma, Italy
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Abstract
Thyroid microcarcinoma, defined as a thyroid tumor measuring 1 cm or less, is an extremely indolent tumor. Papillary microcarcinoma, the most common subtype, is often identified incidentally in a thyroid removed for benign clinical nodules or diffuse processes (eg, thyroiditis). In this clinical situation, over 99% are cured by simple lobectomy. In the less common scenario, the microcarcinoma is the primary lesion to a lymph node metastasis presenting clinically as a neck mass; in this situation, the tumor should be treated as a clinical cancer. Other rare microcarcinomas can occur and, of these, the most recently described is micromedullary carcinoma. In the familial setting, these lesions are identified in prophylactic thyroidectomies and are not unexpected findings. However, when found as sporadic tumors, their implications are still unknown. The histologic features, pathologic mimics, and molecular facets of these microscopic neoplasms are discussed in this review.
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Affiliation(s)
- Zubair W Baloch
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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Giorgadze TA, Baloch ZW, Pasha T, Zhang PJ, Livolsi VA. Lymphatic and blood vessel density in the follicular patterned lesions of thyroid. Mod Pathol 2005; 18:1424-31. [PMID: 15920537 DOI: 10.1038/modpathol.3800452] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The histologic distinction of follicular patterned lesions of thyroid, that is follicular adenoma, follicular carcinoma, and the follicular variant of papillary thyroid carcinoma can be extremely difficult. The differential diagnostic criteria regarding nuclear features of papillary thyroid carcinoma are subjective, resulting in high interobserver variability. Although papillary thyroid carcinoma metastasizes mainly via lymphatic vessels, whereas follicular carcinoma spreads mostly hematogenously, there are no data regarding utility of objective quantitative criteria such as lymphatic and general blood vessel density for the differential diagnosis of these lesions. In this study, 35 follicular patterned lesions of thyroid (14 follicular adenomas, 10 follicular carcinomas, and 11 of the follicular variant of papillary thyroid carcinomas) were evaluated immunohistochemically. An assessment of intra- and peritumoral lymphatic vessel density was performed using novel lymphatic endothelium-specific marker D2-40, and the intra- and peritumoral general vessel density was determined by the panendothelial marker CD31. There were no significant differences in the intra- and/or peritumoral general vessel densities, and peritumoral lymphatic vessel densities among follicular adenoma, follicular carcinoma and the follicular variant of papillary thyroid carcinoma. In contrast, the intratumoral lymphatic vessel density was significantly higher in the follicular variant of papillary thyroid carcinoma than in either follicular adenoma or follicular carcinoma (34.63, 15.04, and 0.11 respectively; P<0.0001). The results of the study show that intratumoral lymphatic vessel density may serve as a useful tool in the differential diagnosis of follicular patterned lesions of thyroid.
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Affiliation(s)
- Tamar A Giorgadze
- Department of Pathology, East Tennessee State University, Johnson City, TN 37604, USA.
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35
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Stabenow E, Tavares MR, Ab'Saber AM, Parra-Cuentas ER, de Matos LL, Eher EM, Capelozzi VL, Ferraz AR. Angiogenesis as an indicator of metastatic potential in papillary thyroid carcinoma. Clinics (Sao Paulo) 2005; 60:233-40. [PMID: 15962085 DOI: 10.1590/s1807-59322005000300009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
UNLABELLED Angiogenesis is new blood vessel formation, a process that can lead to tumor development. Microvessel count has been correlated to metastasis in some neoplasias. PURPOSE To determine if measurement of microvessel density is useful in predicting metastasis to the cervical lymph node and prognosis in patients with papillary thyroid carcinoma. METHODS A retrospective analysis was performed in 30 patients that had undergone total thyroidectomy. They were divided in 2 groups of 15 patients--with and without metastatic disease. Immunohistochemistry was used to detect expression of CD34 in archival paraffin-embedded papillary thyroid tumors, and microvessel density was calculated based on it. Association between microvessel density and the presence of metastasis, according to histological subtype, disease recurrence, and AMES prognostic index groups was determined through statistical analysis. RESULTS The median microvessel density for the patient group without metastasis (200.0 microvessels/mm2) was apparently, but not significantly, less than that observed among metastatic disease patients (254.4 microvessels/mm2) (P=.20). When papillary carcinoma subtypes were analyzed, this difference became significant (P=02). The follicular variant exhibited a greater microvessel density than the other subtypes, independent of metastasis presence. There was an apparent, but not significant, tendency for a larger median microvessel density in the group of patients that presented recurrence (294.4 microvessels/mm2 vs 249.6 microvessels/mm2, P=.11). There was no relationship between risk level and microvessel density: in the low- and high-risk groups, the median MVD was 304.0 microvessels/mm2 and 229.6 microvessels/mm2, respectively (P=.27). CONCLUSIONS The results suggest that angiogenesis is more intense among metastatic tumors in the classic and the tall cell variants, indicating that microvessel count can be an indicator of the potential for metastasis in these subtypes of papillary thyroid carcinoma. Patients that developed recurrent disease had a tendency to exhibit higher angiogenesis; however, there was no association between microvessel density and the AMES prognostic index.
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Affiliation(s)
- Elaine Stabenow
- Head and Neck Surgery Department and Pathology Department, Hospital das Clínicas, Faculty of Medicine, University of São Paulo São Paulo, São Paulo, SP, Brazil.
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Ito Y, Yoshida H, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, Yokozawa T, Matsuzuka F, Kuma K, Miyauchi A. Tie-1 tyrosine kinase expression in human thyroid neoplasms. Histopathology 2004; 44:318-22. [PMID: 15049896 DOI: 10.1111/j.1365-2559.2003.01805.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
AIMS To investigate tie-1 expression in human thyroid neoplasms. Recent studies have demonstrated that receptor-type tyrosine kinases (RTKs) contribute to carcinoma progression. Tie-1 is one of the RTKs and plays a role in angiogenesis, although its pathophysiological significance in human carcinoma is still to be elucidated. METHODS AND RESULTS Immunohistochemical expression of tie-1 was studied in various thyroid neoplasms. Tie-1 immunoreactivity was only occasionally observed in normal follicular cells. In papillary carcinoma, tie-1 was classified as positive in carcinoma cells in 55.7% of the cases and was more frequently expressed in those of smaller size with an absence of a poorly differentiated lesion. In contrast, tie-1 was positive in only 8.3% of anaplastic carcinoma and no cases of follicular carcinoma or adenoma were positive. CONCLUSIONS These results suggest that tie-1 has a role in thyroid tumorigenesis, especially in the early phase of papillary carcinoma, but it is not important in the progression of anaplastic carcinoma or follicular tumour.
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Affiliation(s)
- Y Ito
- Kuma Hospital, Kobe, Japan.
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Pauws E, Veenboer GJM, Smit JWA, de Vijlder JJM, Morreau H, Ris-Stalpers C. Genes differentially expressed in thyroid carcinoma identified by comparison of SAGE expression profiles. FASEB J 2004; 18:560-1. [PMID: 14715705 DOI: 10.1096/fj.03-0101fje] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
To identify transcripts that distinguish malignant from benign thyroid disease serial analysis of gene expression (SAGE) profiles of papillary thyroid carcinoma and of normal thyroid are compared. Of the 21,000 tags analyzed, 204 tags are differentially expressed with statistical significance in the tumor. Thyroid tumor specificity of these transcripts is determined in silico using the tissue preferential expression (TPE) algorithm. TPE values demonstrate that 42 tags of the 204 are thyroid tumor specific. BC013035, a cDNA encoding a novel protein, is up-regulated from 0 to 24 tags in the thyroid tumor SAGE library. In a tissue panel of 30 thyroid tumors and 12 controls, it has an expression pattern similar to thyroid peroxidase, indicating possible involvement of BC013035 in thyroid differentiation. A tag coding for extracellular matrix protein 1 (ECM1) is absent in the normal thyroid SAGE library and present 55 times in the tumor. ECM1, a protein recently associated with angiogenesis and expressed in metastatic breast carcinoma, is up-regulated in 50% of all thyroid carcinoma and absent in normal controls and follicular adenoma. In conclusion, SAGE analysis and subsequent determination of TPE values facilitates the rapid distinction of genes specifically expressed in cancer tissues.
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Affiliation(s)
- Erwin Pauws
- Laboratory of Pediatric Endocrinology, Academic Medical Center, Amsterdam, The Netherlands
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Abstract
Angiogenesis is the process of new blood vessel development from preexisting vasculature. Although vascular endothelium is usually quiescent in the adult, active angiogenesis has been shown to be an important process for new vessel formation, tumor growth, progression, and spread. The angiogenic phenotype depends on the balance of proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and inhibitors, as well as interactions with the extracellular matrix, allowing for endothelial migration. Endocrine glands are typically vascular organs, and their blood supply is essential for normal function and tight control of hormone feedback loops. In addition to metabolic factors such as hypoxia, the process of angiogenesis is also regulated by hormonal changes such as increased estrogen, IGF-I, and TSH levels. By measuring microvascular density, differences in angiogenesis have been related to differences in tumor behavior, and similar techniques have been applied to both benign and malignant endocrine tumors with the aim of identification of tumors that subsequently behave in an aggressive fashion. In contrast to other tumor types, pituitary tumors are less vascular than normal pituitary tissue, although the mechanism for this observation is not known. A relationship between angiogenesis and tumor size, tumor invasiveness, and aggressiveness has been shown in some pituitary tumor types, but not in others. There are few reports on the role of microvascular density or angiogenic factors in adrenal tumors. The mechanism of the vascular tumors, which include adrenomedullary tumors, found in patients with Von Hippel Lindau disease has been well characterized, and clinical trials of antiangiogenic therapy are currently being performed in patients with Von Hippel Lindau disease. Thyroid tumors are more vascular than normal thyroid tissue, and there is a clear correlation between increased VEGF expression and more aggressive thyroid tumor behavior and metastasis. Although parathyroid tissue induces angiogenesis when autotransplanted and PTH regulates both VEGF and MMP expression, there are few studies of angiogenesis and angiogenic factors in parathyroid tumors. An understanding of the balance of angiogenesis in these vascular tumors and mechanisms of vascular control may assist in therapeutic decisions and allow appropriately targeted treatment.
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Affiliation(s)
- Helen E Turner
- Department of Endocrinology, Churchill Hospital, Oxford OX3 7LJ, United Kingdom
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Li C, Gardy R, Seon BK, Duff SE, Abdalla S, Renehan A, O'Dwyer ST, Haboubi N, Kumar S. Both high intratumoral microvessel density determined using CD105 antibody and elevated plasma levels of CD105 in colorectal cancer patients correlate with poor prognosis. Br J Cancer 2003; 88:1424-31. [PMID: 12778073 PMCID: PMC2741032 DOI: 10.1038/sj.bjc.6600874] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
CD105 and its ligand transforming growth factor beta (TGFbeta) are modulators of angiogenesis, which drives tumour growth and metastasis. Tumour microvessel density (MVD) has proven to be an important determinant of prognosis. In this study, we have examined the prognostic value of MVD identified using Mabs to the pan-endothelial marker CD34 and to CD105 in 111 patients with colorectal cancer. The Mab to CD105 preferentially reacts with angiogenic endothelial cells. Of the 111 patients studied, 38 were alive and 73 had died of the disease. The median MVD values counted using anti-CD34 and anti-CD105 were 5 (range 1.40-9.00) and 3.10 (range 0.90-8.00), respectively. Kaplan-Meier survival analysis revealed that only MVD values obtained using CD105 Mab correlated with survival. Patients with a high MVD, above the median (3.10), showed the worst prognosis. A similar outcome was observed when MVD was divided into quartiles. In order to ascertain if this strong expression of CD105 in the tumour vasculature is reflected in patients' plasma, circulating levels of CD105, TGFbeta1 and TGFbeta3 together with the receptor-ligand complexes were quantified in patients with colorectal carcinoma and normal controls. Results showed that except for TGFbeta1, the levels of all other molecules were significantly elevated compared with controls. The levels of CD105 were positively correlated with Dukes' stages. A lower TGFbeta1 level was noted in patients with carcinoma over the controls. Furthermore, TGFbeta3 and CD105/TGFbeta3 complexes were markedly lowered in postoperative compared with preoperative plasma samples. Immunostaining revealed that TGFbeta1 was expressed in cancer cells but TGFbeta3 in the stromal cells, whereas CD105 was exclusively expressed in vascular endothelial cells of tumour blood vessels. In conclusion, this study demonstrates that MVD quantified using a Mab to CD105 is an independent prognostic parameter for survival of patients with colorectal cancer, and that plasma levels of CD105, TGFbeta1, TGFbeta3 and CD105/TGFbeta complexes may be useful markers for assessing disease progression. These data have led us to propose that quantification of these determinants may prove useful to monitor therapeutic efficacy in patients with colorectal cancer, especially those who are being treated with antiangiogenic therapies.
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Affiliation(s)
- C Li
- Department of Pathology, The University of Manchester, Manchester, UK
| | - R Gardy
- Department of Pathology, The University of Manchester, Manchester, UK
| | - B K Seon
- Department of Molecular Immunology, Rosewell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - S E Duff
- Department of Surgery, Christie Hospital, Manchester, UK
| | - S Abdalla
- Department of Immunology, The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada
| | - A Renehan
- Department of Surgery, Christie Hospital, Manchester, UK
| | - S T O'Dwyer
- Department of Surgery, Christie Hospital, Manchester, UK
| | - N Haboubi
- Department of Pathology, Trafford General Hospital, Manchester, UK
| | - S Kumar
- Department of Pathology, The University of Manchester, Manchester, UK
- Department of Pathology, The University of Manchester, Manchester, UK. E-mail:
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Scarpino S, D'Alena FC, Di Napoli A, Ballarini F, Prat M, Ruco LP. Papillary carcinoma of the thyroid: evidence for a role for hepatocyte growth factor (HGF) in promoting tumour angiogenesis. J Pathol 2003; 199:243-50. [PMID: 12533838 DOI: 10.1002/path.1278] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The pattern of vascularization of papillary carcinoma was investigated in tumour sections from 31 cases and in primary cultures from 12 cases. Tumour sections were immunostained for von Willebrand Factor (vWF) to visualize blood vessels; for endothelial-specific nitric-oxide-synthase (EC-NOS), as a marker of endothelial cell activation; and for Ki-67 to evaluate endothelial cell proliferation. It was found that endothelial cells lining venous vessels located in peritumoural fibrous tissue were intensely EC-NOS-positive and occasionally Ki-67-positive. Capillary vessels of tumour papillae were not stained for Ki-67 and were weakly EC-NOS-positive. Primary cultures of papillary carcinoma cells were used as a potential source of factors active on endothelial cells. It was found that thyroid tumour cells contain RNAs for angiopoietin, vascular endothelial growth factor (VEGF), and VEGF-C; moreover, they release large amounts of VEGF into culture supernatants and exert chemotactic activity in vitro for the endothelial cell line SIEC. The ability of papillary carcinoma cells to release angiogenic factors could be stimulated in vitro. Hepatocyte growth factor (HGF; 25 ng/ml) induced a 1.2- to 5-fold increase in the amount of VEGF released by tumour cells and a 1.2- to 4.2-fold increase in the amount of chemotactic activity present in culture supernatants. Met protein, the high affinity HGF-receptor, is overexpressed in a large proportion of cases of papillary carcinoma. These findings are consistent with the possibility that HGF-Met protein interaction is one of the molecular mechanisms promoting the vascularization of papillary carcinoma of the thyroid.
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Affiliation(s)
- Stefania Scarpino
- Dipartimento di Diagnostica di Laboratorio, Ospedale Sant'Andrea, Università La Sapienza, Roma, Italy
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Abstract
Inhibition of angiogenesis has become a target for antineoplastic therapy and for treatment of retinal neovascularization. The presence of somatostatin receptors on tumour cells and on the proliferating vascular endothelium has led to several in vitro and in vivo studies to investigate the antiproliferative and antiangiogenic effects of somatostatin analogues. Currently available data suggest that somatostatin analogues might inhibit angiogenesis directly through somatostatin receptors present on endothelial cells and also indirectly through the inhibition of growth factor secretion such as IGF-I and vascular endothelial growth factor (VEGF) and reducing monocyte chemotaxis. However, beneficial effects on inhibition of neovascularization have been questioned by some studies. More work is therefore required to firmly establish the role of somatostatin analogues as potential antiangiogenic therapy. The currently available somatostatin analogues have high affinity for somatostatin receptor subtype 2 (sst2) and, to a lesser extent, sst5 and sst3. However, because vascular endothelial cells express several types of somatostatin receptors, it will be important to investigate somatostatin analogues with different receptor subtype affinities, which might increase the spectrum of available therapy for tumours.
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Affiliation(s)
- N García de la Torre
- Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
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Kent MS, Griffey SM, Verstraete FJM, Naydan D, Madewell BR. Computer-assisted image analysis of neovascularization in thyroid neoplasms from dogs. Am J Vet Res 2002; 63:363-9. [PMID: 11926179 DOI: 10.2460/ajvr.2002.63.363] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To develop a computer-assisted image analysis procedure for quantitation of neovascularization in formalin-fixed paraffin-embedded specimens of thyroid gland tissue from dogs with and without thyroid gland neoplasia. SAMPLE POPULATION 47 thyroid gland carcinomas, 8 thyroid gland adenomas, and 8 specimens of thyroid tissue from dogs without thyroid gland abnormalities (normal). PROCEDURE Serial tissue sections were prepared and stained with antibodies against human CD31 or factor VIII-related antigen (factor VIII-rag). The areas of highest vascularity were identified in CD31-stained sections, and corresponding areas were then identified in factor VIII-rag-stained sections. Image analysis was used to calculate the total vascular density in each section, and neovascularization, expressed as a percentage, was determined as the absolute value of the total vascular density derived from factor VIII-rag-stained sections minus the vascular density derived from CD31-stained sections. RESULTS Mean vascular density of thyroid gland carcinomas derived from CD31-stained sections was significantly greater than density derived from factor VII I-rag-stained sections. This incremental difference was presumed to represent degree of neovascularization. However, significant differences were not detected between vascular densities derived from CD31 and factor VIII-rag-stained sections for either normal thyroid gland tissue or thyroid gland adenomas. No significant correlations were found between vascular density in thyroid gland carcinomas and survival time following surgery. CONCLUSION AND CLINICAL RELEVANCE A computer-assisted image analysis method was developed for quantifying neovascularization in thyroid gland tumors of dogs. This method may allow identification of dogs with tumors that are most likely to respond to treatment with novel antiangiogenesis agents.
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Affiliation(s)
- Michael S Kent
- Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
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