|
1
|
Wang J, Xu J, Liu X, Li X, Xu Z. A microfluidic chip incorporating magnetic sorting and invasive separation for isolation, culture and telomerase analysis of circulating tumor cells. Talanta 2025; 285:127316. [PMID: 39644673 DOI: 10.1016/j.talanta.2024.127316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/28/2024] [Accepted: 11/30/2024] [Indexed: 12/09/2024]
Abstract
Circulating tumor cells (CTCs) are a crucial indicator of cancer metastasis, and are vital for early diagnosis, disease monitoring, and treatment response evaluation. However, their extremely low concentration and the complexities of isolation techniques pose a significant challenge in capturing and analyzing CTCs. In this study, we developed a novel microfluidic system that integrates magnetic capture and invasive screening onto a single microfluidic chip. By attaching positively charged magnetic nanoparticles to negatively charged CTCs, the magnetic separation of CTCs within the chip effectively eliminates interference from blood cells. A total of 2 mL blood sample can be processed within 3 min, achieving an impressive tumor capture efficiency of 84 %. Using the chip, we also successfully achieved long-term culture of CTCs, and identified CTCs with high activity and invasive potential in blood samples from 11 patients with colorectal cancer. Finally, we analyzed telomerase activity in cultured CTCs on the microfluidic chip. Significantly higher invasive potential and telomerase activity were observed in CTCs from the malignant tumor group compared to the benign group (P < 0.01), highlighting their increased aggressiveness. This study offers a novel approach for efficient CTCs isolation, culture, and telomerase analysis, clarifying the crucial role of telomerase in tumor metastasis and providing profound insights for future research on telomerase-targeted tumor metastasis.
Collapse
Affiliation(s)
- Jie Wang
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Jiali Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Xiaopeng Liu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Xin Li
- Department of Anesthesiology, Liaoning Cancer Hospital and Institute, Shenyang, 110042, PR China
| | - Zhangrun Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China.
| |
Collapse
|
|
2
|
Bollu VS, Chen YC, Zhang F, Gowda K, Amin S, Sharma AK, Schell TD, Zhu J, Robertson GP. Managing telomerase and telomere dysfunction in acral melanoma. Pharmacol Res 2025; 215:107700. [PMID: 40097124 DOI: 10.1016/j.phrs.2025.107700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/04/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
Acral Lentiginous Melanoma is a rare and aggressive subtype of melanoma that commonly affects the palms, soles, and nail beds. It is more prevalent in individuals with darker skin tones, including Asian, African, and Hispanic populations. Unlike cutaneous melanomas, acral melanoma is not associated with UV exposure and has a distinct genetic and molecular profile, underscoring the need for tailored research and treatment strategies. Standard treatments, such as surgery, chemotherapy, immunotherapy, and targeted therapies, have shown limited success for this melanoma subtype, highlighting the urgency of developing more effective interventions. Telomerase is an enzyme that extends telomeres and is a key target in acral melanoma which exhibits' high telomerase activity, driven by mutations in the telomerase reverse transcriptase TERT promoter, which contributes to uncontrolled tumor cell proliferation, cancer cell immortality, and resistance to conventional therapies. Therefore, targeting telomerase presents a promising therapeutic avenue for acral melanoma patients who do not respond well to current treatments. Several approaches for targeting telomerase deregulation have been developed, and their potential for the management of acral melanoma is discussed in this review. Specifically, the promise of telomerase-targeted therapies for acral melanoma is emphasized and explores how these strategies could improve outcomes for patients with this challenging skin cancer. By focusing on the role of telomerase in tumorigenesis and treatment resistance, telomerase-targeted strategies hold potential as a foundational component of therapies for acral melanoma, complementing existing approaches.
Collapse
Affiliation(s)
- Vishnu Sravan Bollu
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Yu-Chi Chen
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Fan Zhang
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA 99202, United States
| | - Krishne Gowda
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Shantu Amin
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Arun K Sharma
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Todd D Schell
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Jiyue Zhu
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA 99202, United States
| | - Gavin P Robertson
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Foreman Foundation for Melanoma Research, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Melanoma and Skin Cancer Center, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Melanoma Therapeutics Program, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
| |
Collapse
|
|
3
|
Wang J, Xu J, Liu X, Tong Y, Xu Z. Establishment of highly metastatic sublines and insights into telomerase expression during tumor metastasis using a microfluidic system. Talanta 2024; 280:126690. [PMID: 39126963 DOI: 10.1016/j.talanta.2024.126690] [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: 06/24/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
Metastasis is an important hallmark of malignant tumors, and telomerase often exhibits high expression in these tumors. Monitoring the real-time dynamics of telomerase will provide valuable insights into its association with tumor metastasis. In this study, we described a microfluidic system for screening highly metastatic sublines based on differential cell invasiveness, investigated telomerase expression in the process of tumor metastasis and explored the genes and signaling pathways involved in tumor metastasis. Cells with different metastasis abilities were efficiently classified into different channels, and the fluorescence imaging visually demonstrates that cells with higher metastasis ability have stronger telomerase activity. In addition, we successfully established the high-metastasis-ability LoVo subline (named as LoVo-H) and low-metastasis-ability LoVo subline (named as LoVo-L) from the human colorectal cancer LoVo cell lines through only one round of selection using the system. The results show that the LoVo-H cells display superior proliferation and invasiveness compared to LoVo-L cells. Furthermore, 6776 differentially expressed genes of LoVo-H compared with LoVo-L were identified by transcriptome sequencing. The genes associated with telomerase activity, cell migration and the epithelial to mesenchymal transition were up-regulated in LoVo-H, and PI3K-Akt signaling pathway, extracellular matrix-receptor interaction and Rap1 signaling pathway were significantly enriched in LoVo-H. This microfluidic system is a highly effective tool for selecting highly metastatic sublines and the LoVo-H subline established through this system presents a promising model for tumor metastasis research. Furthermore, this work preliminarily reveals telomerase expression during tumor metastasis and provides a new strategy for studying tumor metastasis and cancer diagnosis.
Collapse
Affiliation(s)
- Jie Wang
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Jiali Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Xiaopeng Liu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Yuxiao Tong
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Zhangrun Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China.
| |
Collapse
|
|
4
|
Liang C, Zhao R, Du J, Zhao G, Zhang Y. The association between dietary selenium intake and telomere length in hypertension. J Clin Hypertens (Greenwich) 2024; 26:990-996. [PMID: 38967394 PMCID: PMC11301449 DOI: 10.1111/jch.14861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/29/2024] [Accepted: 06/06/2024] [Indexed: 07/06/2024]
Abstract
Telomere length is closely linked to biological aging, oxidative stress, and the development of cardiovascular diseases. This study aimed to assess the association between dietary selenium intake and telomere length in individuals with hypertension. Data on dietary selenium intake were captured through the National Health and Nutrition Examination Survey (NHANES) computer-assisted dietary interview system (CADI). Telomere length determination entailed selecting blood samples from all participants in the NHANES database. The analysis was performed using Analysis System software, with Empower stats utilized for data analysis. Results showed that there was a significant association between dietary selenium intake and telomere length in hypertension, particularly within the female group. In female hypertension cases, a 1 mcg increase in dietary selenium intake corresponded to a telomere length increase of 1.19 bp, even after adjusting for age, race, BMI, marital status, physical activity, energy intake, and stroke history. The relationship between dietary selenium intake and telomere length exhibited a linear pattern in female hypertension patients. This study identified a positive association between dietary selenium intake and telomere length in hypertension, particularly within the female group.
Collapse
Affiliation(s)
- Cui Liang
- Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Ruixue Zhao
- Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jiaqi Du
- Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Guojun Zhao
- Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yanzhou Zhang
- Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| |
Collapse
|
|
5
|
Kamal S, Junaid M, Ejaz A, Bibi I, Akash MSH, Rehman K. The secrets of telomerase: Retrospective analysis and future prospects. Life Sci 2020; 257:118115. [PMID: 32698073 DOI: 10.1016/j.lfs.2020.118115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/06/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022]
Abstract
Telomerase plays a significant role to maintain and regulate the telomere length, cellular immortality and senescence by the addition of guanine-rich repetitive sequences. Chronic inflammation or oxidative stress-induced infection downregulates TERT gene modifying telomerase activity thus contributing to the early steps of gastric carcinogenesis process. Furthermore, telomere-telomerase system performs fundamental role in the pathogenesis and progression of diabetes mellitus as well as in its vascular intricacy. The cessation of cell proliferation in cultured cells by inhibiting the telomerase activity of transformed cells renders the rationale for culling of telomerase as a target therapy for the treatment of metabolic disorders and various types of cancers. In this article, we have briefly described the role of immune system and malignant cells in the expression of telomerase with critical analysis on the gaps and potential for future studies. The key findings regarding the secrets of the telomerase summarized in this article will help in future treatment modalities for the prevention of various types of cancers and metabolic disorders notably diabetes mellitus.
Collapse
Affiliation(s)
- Shagufta Kamal
- Department of Biochemistry, Government College University Faisalabad, Pakistan
| | - Muhammad Junaid
- Department of Biochemistry, Government College University Faisalabad, Pakistan
| | - Arslan Ejaz
- Department of Biochemistry, Government College University Faisalabad, Pakistan
| | - Ismat Bibi
- Department of Chemistry, Islamia University, Bahawalpur, Pakistan
| | | | - Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan.
| |
Collapse
|
|
6
|
Sharma R, Martins N. Telomeres, DNA Damage and Ageing: Potential Leads from Ayurvedic Rasayana (Anti-Ageing) Drugs. J Clin Med 2020; 9:jcm9082544. [PMID: 32781627 PMCID: PMC7465058 DOI: 10.3390/jcm9082544] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023] Open
Abstract
Ageing, while a relentless, unidirectional and pleiotropic phenomenon of life, is a key trigger for several age-related disorders, such as cancer, cataract, osteoporosis, hypertension, cardiovascular (CV), metabolic and even neurodegenerative ailments, including Alzheimer's (AD) and Parkinson's (PD) disease [1] [...].
Collapse
Affiliation(s)
- Rohit Sharma
- Department of Rasashastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
- Correspondence: or (R.S.); (N.M.); Tel.: +91-9816724054 (R.S.); +351-22-5512100 (N.M.)
| | - Natália Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
- Institute for research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, 4200-319 Porto, Portugal
- Correspondence: or (R.S.); (N.M.); Tel.: +91-9816724054 (R.S.); +351-22-5512100 (N.M.)
| |
Collapse
|
|
7
|
Dong K, Zhang Y, Huang JJ, Xia SS, Yang Y. Shorter leucocyte telomere length as a potential biomarker for nonalcoholic fatty liver disease-related advanced fibrosis in T2DM patients. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:308. [PMID: 32355752 PMCID: PMC7186748 DOI: 10.21037/atm.2020.03.10] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Telomere length has been linked to hepatic fibrosis. Type 2 diabetes mellitus (T2DM) is considered as a particular risk for the development of hepatic fibrosis. This study is to explore the association of leucocyte telomere length (LTL) and nonalcoholic fatty liver disease (NAFLD)-related advanced fibrosis in T2DM patients. Methods A total of 442 patients with T2DM were enrolled from Tongji Hospital, Wuhan, China. Clinical features were collected and LTL was measured by Southern blot-based terminal restriction fragment length. Hepatic advanced fibrosis was determined by both the NAFLD fibrosis score (NFS) and fibrosis-4 score (FIB-4). Explanatory factors for advanced fibrosis in T2DM patients were identified using multiple logistic regressions. Results T2DM patients with advanced fibrosis had significant shorter LTL than the no-advanced group. Additionally, LTL, age, male and aminotransferase (ALT) were significantly associated with advanced fibrosis status in T2DM patients. Longer diabetes duration was found to have a strong association with advanced fibrosis in elder T2DM patients. Conclusions Shorter LTL was significantly associated with advanced fibrosis in T2DM patients. Longer diabetes duration was an independent risk factor for advanced fibrosis in old T2DM patients. Shorter LTL may be used as a biomarker for advanced fibrosis in T2DM patients.
Collapse
Affiliation(s)
- Kun Dong
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ye Zhang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiao-Jiao Huang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - San-Shan Xia
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yan Yang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| |
Collapse
|
|
8
|
A telomerase with novel non-canonical roles: TERT controls cellular aggregation and tissue size in Dictyostelium. PLoS Genet 2019; 15:e1008188. [PMID: 31237867 PMCID: PMC6592521 DOI: 10.1371/journal.pgen.1008188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/10/2019] [Indexed: 11/19/2022] Open
Abstract
Telomerase, particularly its main subunit, the reverse transcriptase, TERT, prevents DNA erosion during eukaryotic chromosomal replication, but also has poorly understood non-canonical functions. Here, in the model social amoeba Dictyostelium discoideum, we show that the protein encoded by tert has telomerase-like motifs, and regulates, non-canonically, important developmental processes. Expression levels of wild-type (WT) tert were biphasic, peaking at 8 and 12 h post-starvation, aligning with developmental events, such as the initiation of streaming (~7 h) and mound formation (~10 h). In tert KO mutants, however, aggregation was delayed until 16 h. Large, irregular streams formed, then broke up, forming small mounds. The mound-size defect was not induced when a KO mutant of countin (a master size-regulating gene) was treated with TERT inhibitors, but anti-countin antibodies did rescue size in the tert KO. Although, conditioned medium (CM) from countin mutants failed to rescue size in the tert KO, tert KO CM rescued the countin KO phenotype. These and additional observations indicate that TERT acts upstream of smlA/countin: (i) the observed expression levels of smlA and countin, being respectively lower and higher (than WT) in the tert KO; (ii) the levels of known size-regulation intermediates, glucose (low) and adenosine (high), in the tert mutant, and the size defect's rescue by supplemented glucose or the adenosine-antagonist, caffeine; (iii) the induction of the size defect in the WT by tert KO CM and TERT inhibitors. The tert KO's other defects (delayed aggregation, irregular streaming) were associated with changes to cAMP-regulated processes (e.g. chemotaxis, cAMP pulsing) and their regulatory factors (e.g. cAMP; acaA, carA expression). Overexpression of WT tert in the tert KO rescued these defects (and size), and restored a single cAMP signaling centre. Our results indicate that TERT acts in novel, non-canonical and upstream ways, regulating key developmental events in Dictyostelium.
Collapse
|
|
9
|
Dorajoo R, Chang X, Gurung RL, Li Z, Wang L, Wang R, Beckman KB, Adams-Haduch J, M Y, Liu S, Meah WY, Sim KS, Lim SC, Friedlander Y, Liu J, van Dam RM, Yuan JM, Koh WP, Khor CC, Heng CK. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies. Nat Commun 2019; 10:2491. [PMID: 31171785 PMCID: PMC6554354 DOI: 10.1038/s41467-019-10443-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 05/09/2019] [Indexed: 01/02/2023] Open
Abstract
Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.
Collapse
Affiliation(s)
- Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
| | - Xuling Chang
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, 119074, Singapore
| | - Resham Lal Gurung
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, 768828, Singapore
| | - Zheng Li
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
| | - Ling Wang
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
| | - Renwei Wang
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
| | - Kenneth B Beckman
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Jennifer Adams-Haduch
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
| | - Yiamunaa M
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, 768828, Singapore
| | - Sylvia Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, 768828, Singapore
| | - Wee Yang Meah
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
| | - Kar Seng Sim
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
| | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, 768828, Singapore
- Diabetes Centre, Khoo Teck Puat Hospital, Singapore, 768828, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117549, Singapore
| | - Yechiel Friedlander
- School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, 12272, Israel
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Rob M van Dam
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117549, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Jian-Min Yuan
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117549, Singapore
- Health Systems and Services Research, Duke-NUS Medical School Singapore, Singapore, 169857, Singapore
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 169856, Singapore.
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
- Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, 119074, Singapore.
| |
Collapse
|
|
10
|
Zgheib NK, Sleiman F, Nasreddine L, Nasrallah M, Nakhoul N, Isma'eel H, Tamim H. Short Telomere Length is Associated with Aging, Central Obesity, Poor Sleep and Hypertension in Lebanese Individuals. Aging Dis 2018; 9:77-89. [PMID: 29392083 PMCID: PMC5772860 DOI: 10.14336/ad.2017.0310] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 03/10/2017] [Indexed: 12/20/2022] Open
Abstract
In Lebanon, data stemming from national cross-sectional surveys indicated significant increasing trends in the prevalence of cardiovascular diseases and associated behavioral and age-related risk factors. To our knowledge, no data are available on relative telomere length (RTL) as a potential biomarker for age-related diseases in a Lebanese population. The aim of this study was to evaluate whether there is an association between RTL and demographic characteristics, lifestyle habits and diseases in the Lebanese. This was a cross-sectional study of 497 Lebanese subjects. Peripheral blood RTL was measured by amplifying telomere and single copy gene using real-time PCR. Mean ± SD RTL was 1.42 ± 0.83, and it was categorized into 3 tertiles. Older age (P=0.002) and wider waist circumference (WC) (P=0.001) were statistically significantly associated with shorter RTL. Multinomial logistic regression showed that subjects who had some level of sleeping difficulty had a statistically significantly shorter RTL when compared to those with no sleeping difficulties at all [OR (95% CI): 2.01 (1.11-3.62) in the first RTL tertile]. Importantly, statistically significantly shorter RTL was found with every additional 10 cm of WC [OR (95% CI): 1.30 (1.11-1.52) for first RTL tertile]. In addition, and after performing the multivariate logistic regression and adjusting for “predictors” of RTL, the odds of having hypertension or being treated for hypertension were higher in patients who had shorter RTL: OR (95% CI): 2.45 (1.36-4.44) and 2.28 (1.22-4.26) in the first RTL tertiles respectively with a similar trend, though not statistically significant, in the second RTL tertiles. This is the first study in Lebanon to show an association between age, central obesity, poor sleep and hypertension and RTL. It is hoped that telomere length measurement be potentially used as a biomarker for biological age and age-related diseases and progression in the Lebanese.
Collapse
Affiliation(s)
- Nathalie K Zgheib
- 1Department of Pharmacology & Toxicology, Faculty of Medicine, American University of Beirut, Lebanon
| | - Fatima Sleiman
- 1Department of Pharmacology & Toxicology, Faculty of Medicine, American University of Beirut, Lebanon
| | - Lara Nasreddine
- 2Department of Nutrition & Food Sciences, Faculty of Agriculture and Food Sciences, American University of Beirut, Lebanon
| | - Mona Nasrallah
- 3Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Lebanon
| | - Nancy Nakhoul
- 3Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Lebanon
| | - Hussain Isma'eel
- 3Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Lebanon
| | - Hani Tamim
- 3Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Lebanon.,4Clinical Research Institute, Faculty of Medicine, American University of Beirut Medical Center, Lebanon
| |
Collapse
|
|
11
|
The Maintenance of Telomere Length in CD28+ T Cells During T Lymphocyte Stimulation. Sci Rep 2017; 7:6785. [PMID: 28754961 PMCID: PMC5533788 DOI: 10.1038/s41598-017-05174-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 05/24/2017] [Indexed: 12/21/2022] Open
Abstract
Telomerase activity is not readily detected in resting human T lymphocytes, however upon antigen presentation, telomerase is transiently upregulated. Presently, it is not known if telomerase activation is necessary for the proliferation of T cells or for the maintenance of telomere lengths. In this study, we found that telomerase activation is not required for the short- term proliferation of T cells and that telomeres progressively shorten in a heterogeneous population of T cells, even if telomerase is detected. By measuring telomerase activity at the single-cell level using quantitative ddPCR techniques (ddTRAP) and by monitoring changes in the shortest telomeres with more sensitive telomere length measurement assays, we show that only a subset of CD28+ T-cells have robust telomerase activity upon stimulation and are capable of maintaining their telomere lengths during induced proliferation. The study of this T-cell subset may lead to a better understanding on how telomerase is regulated and functions in immune cells.
Collapse
|
|
12
|
Al-Asbahy WM, Usman M, Arjmand F, Shamsi M, Tabassum S. A dinuclear copper(II) complex with piperazine bridge ligand as a potential anticancer agent: DFT computation and biological evaluation. Inorganica Chim Acta 2016. [DOI: 10.1016/j.ica.2016.02.046] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
13
|
Raguraman V, Subramaniam JR. <i>Withania somnifera</i> Root Extract Enhances Telomerase Activity in the Human HeLa Cell Line. ACTA ACUST UNITED AC 2016. [DOI: 10.4236/abb.2016.74018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
14
|
BAKRY RANIA, EL-SAYED MOHAMEDI, HAMZA HESHAMM, HASSAN KHALEDH. Pretreatment levels of serum osteoprotegerin and p53 protein and urine telomerase as prognostic factors affecting survival in Egyptian bladder cancer patients. Oncol Lett 2016; 11:823-830. [PMID: 26870291 PMCID: PMC4727083 DOI: 10.3892/ol.2015.3925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 08/27/2015] [Indexed: 12/18/2022] Open
Abstract
A non-invasive marker is required for the diagnosis and follow-up of patients with bladder cancer. The aim of the current study was to evaluate the potential prognostic significance of serum osteoprotegerin (OPG), p53 protein and urine telomerase in patients with bladder cancer. For all patients, serum levels of OPG and p53 protein were determined using enzyme-linked immunosorbent assay (ELISA), and urine telomerase was assessed using a polymerase chain reaction ELISA technique. Patients were assigned into group 1 (cystectomy and adjuvant radiotherapy) or group 2 (transurethral resection and chemoradiotherapy). The results revealed that serum OPG and p53, and urine telomerase levels were significantly higher in bladder cancer patients compared with in healthy individuals (P<0.0001). High serum OPG was associated with significantly lower overall survival and disease-free survival rates (both P=0.001), and was correlated with advanced tumor stages (P<0.0001), high tumor grades (P<0.0001) and the occurrence of disease relapse (P=0.001). Serum p53 and urine telomerase did not demonstrate prognostic significance. These findings indicate that serum OPG level may be used as a diagnostic tool and a prognostic variable for patients with muscle invasive bladder cancer. Future trials are required to elucidate its therapeutic role in such patients.
Collapse
Affiliation(s)
- RANIA BAKRY
- Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
| | - MOHAMED I. EL-SAYED
- Department of Radiotherapy, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
| | - HESHAM M. HAMZA
- Department of Surgical Oncology, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
| | - KHALED H. HASSAN
- Department of Biochemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11566, Egypt
| |
Collapse
|
|
15
|
Abliz G, Mijit F, Hua L, Abdixkur G, Ablimit T, Amat N, Upur H. Anti-carcinogenic effects of the phenolic-rich extract from abnormal Savda Munziq in association with its cytotoxicity, apoptosis-inducing properties and telomerase activity in human cervical cancer cells (SiHa). Altern Ther Health Med 2015; 15:23. [PMID: 25880193 PMCID: PMC4331379 DOI: 10.1186/s12906-015-0530-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 01/16/2015] [Indexed: 11/10/2022]
Abstract
BACKGROUND Abnormal Savda Munziq (ASMq) is a herbal preparation used in Traditional Uighur Medicine for the treatment cancer. The polyphenol is main compounds contained in ASMq preparation responsible for anticancer effect of ASMq. METHODS In this study,Real-time quantitative Polymerase Chain Reaction (RT-PCR) assay, MTT assay and flow cytometry were used to investigate the effect of polyphenol of ASMq on cell viability and the potential of the phenolic rich extracts of ASMq to induce apoptosis in human cervical cancer cells SiHa and its effects on telomerase activity were investigated. Cellular morphological change was observed by phase contrast microscopy. The MTT cell viability data revealed that treatment with phenolic rich extracts at 75 ~ 175 μg/ml significantly inhibited the viability and proliferation of cells, and these effects occurred in a concentration-dependent manner and time dependent manner (P < 0.01). RESULTS The phenolic rich extracts can induce apoptosis of SiHa cells, can increase the apoptosis rate in a concentration-dependent manner and time dependent manner (P < 0.01). Growth inhibition and apoptosis induction by phenolic rich extracts treatment on SiHa cells was associated with down-regulation of anti-apoptotic Bcl-2 expression and telomerase (P < 0.05) and Survivin expression. In addition, phenolic rich extracts exerted a dose-dependent induction of FHIT expression. CONCLUSION These results suggest that phenolic rich extracts may have anti-tumor effects in human cervical cancer through cytotoxicity, apoptosis-inducing properties and telomerase activity.
Collapse
|
|
16
|
Yamaguchi DT. “Ins” and “Outs” of mesenchymal stem cell osteogenesis in regenerative medicine. World J Stem Cells 2014; 6:94-110. [PMID: 24772237 PMCID: PMC3999785 DOI: 10.4252/wjsc.v6.i2.94] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Repair and regeneration of bone requires mesenchymal stem cells that by self-renewal, are able to generate a critical mass of cells with the ability to differentiate into osteoblasts that can produce bone protein matrix (osteoid) and enable its mineralization. The number of human mesenchymal stem cells (hMSCs) diminishes with age and ex vivo replication of hMSCs has limited potential. While propagating hMSCs under hypoxic conditions may maintain their ability to self-renew, the strategy of using human telomerase reverse transcriptase (hTERT) to allow for hMSCs to prolong their replicative lifespan is an attractive means of ensuring a critical mass of cells with the potential to differentiate into various mesodermal structural tissues including bone. However, this strategy must be tempered by the oncogenic potential of TERT-transformed cells, or their ability to enhance already established cancers, the unknown differentiating potential of high population doubling hMSCs and the source of hMSCs (e.g., bone marrow, adipose-derived, muscle-derived, umbilical cord blood, etc.) that may provide peculiarities to self-renewal, differentiation, and physiologic function that may differ from non-transformed native cells. Tissue engineering approaches to use hMSCs to repair bone defects utilize the growth of hMSCs on three-dimensional scaffolds that can either be a base on which hMSCs can attach and grow or as a means of sequestering growth factors to assist in the chemoattraction and differentiation of native hMSCs. The use of whole native extracellular matrix (ECM) produced by hMSCs, rather than individual ECM components, appear to be advantageous in not only being utilized as a three-dimensional attachment base but also in appropriate orientation of cells and their differentiation through the growth factors that native ECM harbor or in simulating growth factor motifs. The origin of native ECM, whether from hMSCs from young or old individuals is a critical factor in “rejuvenating” hMSCs from older individuals grown on ECM from younger individuals.
Collapse
|
|
17
|
Shalaby T, Fiaschetti G, Nagasawa K, Shin-ya K, Baumgartner M, Grotzer M. G-quadruplexes as potential therapeutic targets for embryonal tumors. Molecules 2013; 18:12500-37. [PMID: 24152672 PMCID: PMC6269990 DOI: 10.3390/molecules181012500] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 09/18/2013] [Accepted: 09/25/2013] [Indexed: 12/27/2022] Open
Abstract
Embryonal tumors include a heterogeneous group of highly malignant neoplasms that primarily affect infants and children and are characterized by a high rate of mortality and treatment-related morbidity, hence improved therapies are clearly needed. G-quadruplexes are special secondary structures adopted in guanine (G)-rich DNA sequences that are often present in biologically important regions, e.g. at the end of telomeres and in the regulatory regions of oncogenes such as MYC. Owing to the significant roles that both telomeres and MYC play in cancer cell biology, G-quadruplexes have been viewed as emerging therapeutic targets in oncology and as tools for novel anticancer drug design. Several compounds that target these structures have shown promising anticancer activity in tumor xenograft models and some of them have entered Phase II clinical trials. In this review we examine approaches to DNA targeted cancer therapy, summarize the recent developments of G-quadruplex ligands as anticancer drugs and speculate on the future direction of such structures as a potential novel therapeutic strategy for embryonal tumors of the nervous system.
Collapse
Affiliation(s)
- Tarek Shalaby
- Division of Oncology, University Children's Hospital of Zurich, Zurich 8032, Switzerland.
| | | | | | | | | | | |
Collapse
|
|
18
|
Wang L, Yao M, Dong Z, Zhang Y, Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol 2013; 35:9-20. [PMID: 24006223 PMCID: PMC3907675 DOI: 10.1007/s13277-013-1141-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 08/23/2013] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies worldwide with a multifactorial, multistep, complex process and poor prognosis. Its early diagnosis and metastasis monitoring are of the utmost importance. Hepatoma tissues synthesize various tumor-related proteins, genes, enzymes, microRNA, etc. and then secrete into the blood. Detections of circulating biomarkers are useful to find tumor at an early stage or monitor metastasis after postoperative treatment. This paper summarizes recent studies of specific biomarkers at early diagnosis or in monitoring metastasis or postoperative recurrence of HCC.
Collapse
Affiliation(s)
- Li Wang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | | | | | | | | |
Collapse
|
|
19
|
Detection of human telomerase reverse transcriptase mRNA in cells obtained by lavage of the pleura is not associated with worse outcome in patients with stage I/II non-small cell lung cancer: results from Cancer and Leukemia Group B 159902. J Thorac Cardiovasc Surg 2012; 146:206-11. [PMID: 23026566 DOI: 10.1016/j.jtcvs.2012.08.059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 08/16/2012] [Accepted: 08/23/2012] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Previous studies suggest that cytologic analysis of cells obtained by lavage of the pleural surfaces at the time of resection of non-small cell lung cancer can identify patients at risk for recurrence. Because telomerase gene expression has been associated with worse outcome in non-small cell lung cancer, we hypothesized that identification of cells obtained from pleural lavage that express telomerase would identify patients at risk for recurrent disease. METHODS Patients with presumed non-small cell lung cancer underwent thoracotomy with curative intent. Cells obtained by lavage of the pleural surfaces were analyzed for telomerase catalytic subunit human telomerase reverse transcriptase mRNA expression using reverse transcriptase polymerase chain reaction. RESULTS A total of 194 patients with stage I/II non-small cell lung cancer had adequate samples, and median follow-up was 60 months (17-91 months). By using Cox models, no statistical differences were found between human telomerase reverse transcriptase-negative and positive patients in disease-free survival (hazard ratio, 1.28; 95% confidence interval, 0.85-1.94; log-rank test, P = .2349) or overall survival (hazard ratio, 1.13; 95% confidence interval, 0.72-1.79; log-rank test, P = .5912) CONCLUSIONS: Detection of human telomerase reverse transcriptase in cells obtained from pleural lavage of patients with stage I/II non-small cell lung cancer does not identify patients at risk for recurrent disease.
Collapse
|
|
20
|
Knockdown of hTERT alters biophysical properties of K562 cells resulting in decreased migration rate in vitro. Cell Biochem Biophys 2012; 61:595-603. [PMID: 21833675 DOI: 10.1007/s12013-011-9242-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
It has been shown that 90% of tumors, including hematological malignant tumors and leukemia, have much higher levels of telomerase expression than normal cells. To investigate the effect of telomerase on leukemia cells, we transfected K562, a human erythroleukemia cell line with an antisense-hTERT (human telomerase reverse transcriptase) cDNA vector, and examined the biological and biophysical properties of the stably transfected cells (referred to as KAT). Un-transfected cells (K562) and cells transfected with the empty vector (referred to as KC) were used as controls. Cell growth curve and (3)H-TdR test showed that the growth rate and DNA synthesis of KAT decreased compared with those of K562 and KC cells. Apoptosis and cell cycle distribution in KAT cells under normal culture condition were similar to those of K562 and KC cells, but changed after serum deprivation. KAT cells had significantly different biophysical characteristics from K562 and KC in terms of cell electrophoresis, membrane fluidity, membrane fluidity, and viscoelasticity. Furthermore, the transendothelial migration rate of KAT was much lower than those of K562 and KC cells. Confocal microscopy showed that KAT cells had higher F-actin content, suggesting the reorganization of cytoskeleton. Flow cytometry analysis revealed a lowered intracellular calcium concentration and CD71 expression, explaining the high F-actin content in KAT cells. In conclusion, we found that the knockdown of hTERT in K562 cells changed their cytoskeleton and biophysical features, and reduced the cell migration.
Collapse
|
|
21
|
Breheny D, Oke O, Faux SP. The use of in vitro systems to assess cancer mechanisms and the carcinogenic potential of chemicals. Altern Lab Anim 2011; 39:233-55. [PMID: 21777038 DOI: 10.1177/026119291103900301] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Carcinogenesis is a highly complex, multi-stage process that can occur over a relatively long period before its clinical manifestation. While the sequence in which a cancer cell acquires the necessary traits for tumour formation can vary, there are a number of mechanisms that are common to most, if not all, cancers across the spectrum of possible causes. Many aspects of carcinogenesis can be modelled in vitro. This has led to the development of a number of mechanistically driven, cell-based assays to assess the pro-carcinogenic and anti-carcinogenic potential of chemicals. A review is presented of the current in vitro models that can be used to study carcinogenesis, with examples of cigarette smoke testing in some of these models, in order to illustrate their potential applications. We present an overview of the assays used in regulatory genotoxicity testing, as well as those designed to model other aspects that are considered to be hallmarks of cancer. The latter assays are described with a view to demonstrating the recent advances in these areas, to a point where they should now be considered for inclusion in an overall testing strategy for chemical carcinogens.
Collapse
|
|
22
|
Singh M, Singh N. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells. Mol Cell Biochem 2010; 347:1-11. [DOI: 10.1007/s11010-010-0606-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Accepted: 09/28/2010] [Indexed: 02/07/2023]
|
|
23
|
Singh M, Singh N. Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells. Mol Cell Biochem 2009; 325:107-19. [DOI: 10.1007/s11010-009-0025-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2008] [Accepted: 01/15/2009] [Indexed: 01/11/2023]
|
|
24
|
Techangamsuwan S, Kreutzer R, Kreutzer M, Imbschweiler I, Rohn K, Wewetzer K, Baumgärtner W. Transfection of adult canine Schwann cells and olfactory ensheathing cells at early and late passage with human TERT differentially affects growth factor responsiveness and in vitro growth. J Neurosci Methods 2008; 176:112-20. [PMID: 18822316 DOI: 10.1016/j.jneumeth.2008.08.030] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2008] [Revised: 08/21/2008] [Accepted: 08/25/2008] [Indexed: 11/18/2022]
Abstract
Adult canine Schwann cells and olfactory ensheathing cells (OECs) are closely related cell types that are considered attractive candidates for translational studies of neural repair. To establish a reliable cell source by comparing the in vitro properties of immortalized Schwann cells and OECs for transplantation purposes, we transfected both cell types with human telomerase reverse transcriptase (hTERT). Ectopic hTERT expression has been shown to induce immortalization of various cell types without substantial alterations of their phenotypes. Schwann cells and OECs were isolated from adult dogs, transfected with hTERT at early (P4) and late passage (P26), characterized regarding in vitro proliferation, antigenic expression and senescence-associated genes in the presence and absence of fibroblast growth factor-2 (FGF-2). Ectopic hTERT expression in late passage glia treated with but not without FGF-2 prevented the decline in proliferation observed in non-transfected cells. Immortalization did not alter p75(NTR) and GFAP but O4 and A2B5 expression. Contrary to this, early passage hTERT transfection significantly reduced proliferation independent of FGF-2 and lowered expression of O4 and GFAP in both cell types. Transfection did not alter mRNA expression of senescence-associated genes such as p53 and p16. No substantial differences were found between Schwann cells and OECs underscoring the close relationship of both cell types. Taken together, we established a stable source of adult canine Schwann cells and OECs and demonstrated that the effects of hTERT expression on in vitro growth and growth factor responsiveness depend on the replicative age.
Collapse
Affiliation(s)
- Somporn Techangamsuwan
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Zhang C, Guo X, Jiang G, Zhang L, Yang Y, Shen F, Wu M, Wei L. CpG island methylator phenotype association with upregulated telomerase activity in hepatocellular carcinoma. Int J Cancer 2008; 123:998-1004. [PMID: 18546260 DOI: 10.1002/ijc.23650] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CpG island methylator phenotype (CIMP) involves the targeting of multiple genes by promoter hypermethylation. Telomerase plays an important role in the development of cellular immortality and oncogenesis. To gain insight into the role of epigenetic aberration of telomerase-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in HCC. We examined the promoter methylation status of 9 genes associated with telomerase activity in 120 HCC, 120 cirrhosis tissues and 10 normal liver tissues by methylation-specific PCR. Assay of telomerase activity was by TRAP-ELISA. The frequency of promoter methylation of each gene was P21 63.3%, P15 42.5%, P16 62.5%, P53 14.2%, RB 32.5%, P27 48.3%, WTI 54.2%, E2F-1 70.8% and P300 65.8% of 120 HCC. Methylation status of P21, P15, P16, WTI and E2F-1 was significantly associated with HCC and nontumor tissues (p < 0.05). CIMP+ was detected in 61.7% (74/120) HCC and 15% (18/120) cirrhosis tissues, no CIMP+ was present in normal liver tissues (p < 0.001). A significant difference between CIMP status and metastasis was been found in HCC (p < 0.001). Results showed that 94.6% (70/74) HCC and 55.6% (10/18) cirrhosis patients with CIMP+ show expression of high telomerase activity than 45.5% (10/22) HCC and 6.25% (1/16) cirrhosis patients with CIMP- (p < 0.001). CIMP lead to high levels of expression of telomerase activity through the simultaneous inactivation of multiple genes associated with telomerase activity by concordant methylation.
Collapse
Affiliation(s)
- Changsong Zhang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China
| | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Yao DF, Wu W, Yao M, Qiu LW, Wu XH, Su XQ, Zou L, Yao DB, Meng XY. Dynamic alteration of telomerase expression and its diagnostic significance in liver or peripheral blood for hepatocellular carcinoma. World J Gastroenterol 2006; 12:4966-72. [PMID: 16937491 PMCID: PMC4087398 DOI: 10.3748/wjg.v12.i31.4966] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the dynamic alteration of telomerase expression during development of hepatocellular carcinoma (HCC) and its diagnostic implications in liver tissues or peripheral blood mononuclear cells for HCC.
METHODS: Dynamic expressions of liver telomerase during malignant transformation of hepatocytes were observed in Sprague-Dawly (SD) rats fed with 0.05% of 2-fluoenyacetamide (2-FAA). Total RNA and telomerase were extracted from rat or human liver tissues. The telomerase activities in livers and in circulating blood were detected by a telomeric repeat amplification protocol-enzyme-linked immunosorbent assay (TRAP-ELISA), and its diagnostic value was investigated in patients with benign or malignant liver diseases.
RESULTS: The hepatoma model displayed the dynamic expression of hepatic telomerase during HCC development. The telomerase activities were consistent with liver total RNA levels (r = 0.83, P < 0.01) at the stages of degeneration, precancerosis, and cancerization of hepatocytes. In HCC patients, the telomerase levels in HCC tissues were significantly higher than in their adjacent non-cancerous tissues, but liver total RNA levels were lower in the former than in the latter. Although the circulating telomerase of HCC patients was abnormally expressed among patients with chronic liver diseases, the telomerase activity was a non-specific marker for HCC diagnosis, because the incidence was 15.7% in normal control, 25% in chronic hepatitis, 45.9% in liver cirrhosis, and 85.2% in HCC, respectively when absorbance value of telomerase activity was more than 0.2. If the value was over 0.6, the incidence was 60% in HCC group and 0% in any of the others (P < 0.01) except in two cases with liver cirrhosis. However, the combination of circulating telomerase with serum alpha-fetoprotein level could increase the positive rate and the accuracy (92.6%, 125 of 135) of HCC diagnosis.
CONCLUSION: The overexpression of telomerase is associated with HCC development, and its abnormality in liver tissues or in peripheral blood could be a useful marker for diagnosis and prognosis of HCC.
Collapse
Affiliation(s)
- Deng-Fu Yao
- Research Center of Clinical Molecular Biology, Affiliated Hospital, Nantong University, Nantong 226001, Jiangsu Province, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Binz N, Shalaby T, Rivera P, Shin-ya K, Grotzer MA. Telomerase inhibition, telomere shortening, cell growth suppression and induction of apoptosis by telomestatin in childhood neuroblastoma cells. Eur J Cancer 2005; 41:2873-81. [PMID: 16253503 DOI: 10.1016/j.ejca.2005.08.025] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2005] [Revised: 08/05/2005] [Accepted: 08/16/2005] [Indexed: 11/23/2022]
Abstract
Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous system and is the most common extracranial solid tumour in childhood. Unfavourable tumours are characterised not only by structural changes, including 1p deletion and amplification of the MYCN proto-oncogene, but also by high telomerase activity. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. In this study, we examined telomestatin, a G-quadruplex interactive agent, for its ability to inhibit telomere maintenance of neuroblastoma cells. Telomere length was determined by the terminal restriction fragment method, telomerase activity was measured by a quantitative telomeric repeat amplification protocol, and the expression of human telomerase by quantitative real-time polymerase chain reaction (RT-PCR). Short-term treatment with telomestatin resulted in dose-dependent cytotoxicity and induction of apoptosis. Long-term treatment with telomestatin at non-cytotoxic, but still telomerase activity-inhibiting, concentrations resulted in telomere shortening, growth arrest and induction of apoptosis. These results suggest that the effect of telomestatin is dose-dependent and at least 2-fold. Prolonged low-dose treatment with telomestatin limits the cellular lifespan of NB cells through disruption of telomere maintenance.
Collapse
Affiliation(s)
- N Binz
- Department of Oncology, University Children's Hospital of Zurich, Steinwiesstrasse 75, Hospital, 8032 Zurich, Switzerland
| | | | | | | | | |
Collapse
|
|
28
|
Piao YF, He M, Shi Y, Tang TY. Relationship between microvessel density and telomerase activity in hepatocellular carcinoma. World J Gastroenterol 2004; 10:2147-9. [PMID: 15237456 PMCID: PMC4572355 DOI: 10.3748/wjg.v10.i14.2147] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the relationship between microvessel density (MVD), telomerase activity and biological characteristics in hepatocellular carcinoma (HCC).
METHODS: S-P immunohistochemical method and telomeric repeat amplification protocol (TRAP) were respectively used to analyze the MVD and telomerase activity in 58 HCC and adjacent normal tissues.
RESULTS: The MVD in HCC with metastasis, lower differentiation or without intact capsule was significantly higher than that in HCC with intact capsule, higher differentiation, or without metastasis. While MVD had no relationship with tumor size, hepatic virus infection and other clinical factors. Telomerase activity was related to differentiation degree, but not to tumor size or histological grade. MVD in HCC with telomerase activity was higher than that in HCC without telomerase activity.
CONCLUSION: MVD and telomerase activity may serve as diagnostic criteria of HCC in earlier stage. Meanwhile, there may be a cooperative effect between MVD and telomerase on the growth and metastasis of HCC.
Collapse
Affiliation(s)
- Yun-Feng Piao
- Department of Gastroenterology, First Hospital of Jilin University, No.1 Xinmin Road, Changchun 130021, Jilin Province, China
| | | | | | | |
Collapse
|
|
29
|
Yu HP, Xu SQ, Lu WH, Li YY, Li F, Wang XL, Su YH. Telomerase activity and expression of telomerase genes in squamous dysplasia and squamous cell carcinoma of the esophagus. J Surg Oncol 2004; 86:99-104. [PMID: 15112252 DOI: 10.1002/jso.20050] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Telomerase maintains telomere length and is considered to be necessary for the indefinite proliferation of human cells. Activation of telomerase plays a key role in the malignant transformation process. The aim of this study was to study the regulation of telomerase, and to explore the possibility of telomerase as a biomarker in squamous carcinogenesis of the esophagus. METHODS Twenty-nine esophageal squamous cell carcinomas (ESCC) and its corresponding adjacent normal tissues, and 47 epithelial squamous dysplasia tissues were analyzed by the reverse transcriptase-polymerase chain reaction (RT-PCR) technique for the mRNA expression of three major telomerase subunits: human telomerase RNA (hTR), telomerase protein component 1 (TP1), and human telomerase reverse transcriptase (hTERT) and by telomeric repeat amplification protocol assay (TRAP) for telomerase activity. RESULTS For the expression of hTR and TP1 mRNA, there were no significant differences among ESCC, dysplasia and normal tissues (P > 0.05). In contrast, hTERT mRNA expression was detected in 28 of 29 ESCC (96.6%), in 23 of 47 dysplasia (48.9%), and only in two of 29 normal tissues (7.5%). Telomerase activity was positive in 25 of 29 ESCC (86.2%), in 21 of 47 (44.7%) epithelial dysplasia tissues, and in none of normal tissue. All together, 95 of 105 cases (90.48%) were concordant for both results, i.e., telomerase activity positive and hTERT positive or telomerase activity negative and hTERT negative tissues, and telomerase activity correlated with hTERT mRNA expression (P < 0.001). CONCLUSIONS Higher telomerase activity and hTERT mRNA expression were shown during an early stage in the esophageal carcinogenesis. Activation of telomerase activity was strongly correlated with hTERT mRNA expression, suggesting hTERT is a major regulator of telomerase activity, and telomerase activation may play a critical role in esophageal carcinogenesis. Therefore, telomerase, especially hTERT can be used as a potential molecular biomarker of ESCC.
Collapse
Affiliation(s)
- Hong-Ping Yu
- Institute of Environmental Medicine, Tongji Medical College, Wuhan, Hubei Province, China
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Didiano D, Shalaby T, Lang D, Grotzer MA. Telomere maintenance in childhood primitive neuroectodermal brain tumors. Neuro Oncol 2004; 6:1-8. [PMID: 14769133 PMCID: PMC1871965 DOI: 10.1215/s1152851703000176] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Primitive neuroectodermal tumors (PNETs), including medulloblastoma (PNET/MB) and supratentorial PNET (sPNET), are the most common malignant brain tumors of childhood. The stabilization of telomere lengths by telomerase activation is an important step in carcinogenesis and cell immortalization. Epigallocatechin gallate (EGCG), the major polyphenol in green tea, is a telomerase inhibitor with antiproliferative and anticarcinogenic effects against different types of cancer. In this study, we used real-time reverse transcriptase-polymerase chain reaction to measure the mRNA expression of the human telomerase reverse transcriptase (hTERT) in 50 primary PNET samples (43 PNET/MB, 7 sPNET), 14 normal human brain samples, and 6 human PNET cell lines. Compared to normal human cerebellum, 38/50 (76%) primary PNET samples had >or= 5-fold upregulated hTERT mRNA expression. We then examined PNET cell lines for telomerase activity using a quantitative telomeric repeat amplification protocol (TRAP), and for telomere length using terminal restriction fragment analysis. While a positive correlation between hTERT mRNA expression and telomerase activity was detected in PNET cell lines, no correlation was found between telomerase activity and telomere length. Treatment of PNET cell lines with EGCG resulted in a dose-dependent inhibition of telomerase activity at micromolar levels. Although EGCG displayed strong proliferation inhibitory effects against TRAP-positive PNET cell lines, it had no significant effect against TRAP-negative D425 cells. These results provide evidence for a possible role of telomerase in the pathogenesis of most PNETs and indicate that subsets of PNETs maintain telomere length by alternative mechanisms. Inhibition of telomerase function represents a novel experimental therapeutic strategy in childhood PNETs that warrants further investigation.
Collapse
Affiliation(s)
- Domenico Didiano
- Send correspondence to Michael Grotzer, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland (
)
| | | | | | | |
Collapse
|
|
31
|
Lages CS, Etienne O, Comte J, Gauthier LR, Granotier C, Pennarun G, Boussin FD. Identification of alternative transcripts of theTRF1/Pin2 gene. J Cell Biochem 2004; 93:968-79. [PMID: 15389875 DOI: 10.1002/jcb.20235] [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: 11/06/2022]
Abstract
TRF1 and Pin2 play an essential role in telomere homeostasis, by regulating telomere maintenance. They are generated from the same gene, TRF1/Pin2, by alternative splicing but no functional differences between these proteins have been demonstrated. We report here the detection of new alternative transcripts of the TRF1/Pin2 gene in peripheral blood lymphocytes resulting from a 76 nt insertion. Real-time RT-PCR showed that these transcripts were also produced in various normal human cells and tissues and in immortalized cell lines, but at levels lower (by a factor of 8-111) than those for the TRF1 and Pin2 transcripts. These new transcripts are predicted to encode polypeptides identical to TRF1/Pin2 at the C-terminal end but entirely lacking the acid domain and the amino-terminal part of the homodimerization domain of TRF1/Pin2. These proteins, fused at their N-terminal ends to enhanced green fluorescent protein (EGFP), were found to be located at telomeres and to induce apoptosis in cell lines with short telomeres, thereby displaying similar activity to TRF1/Pin2. However, these putative proteins lack regions important for interactions with other proteins and for homodimerization. Unlike TRF1/Pin2, they were unable to interact with tankyrase 1, suggesting that these proteins may play a role in telomere homeostasis different from those of TRF1/Pin2. The production of these alternative transcripts was down-regulated in peripheral blood lymphocytes following PHA-p activation, suggesting a possible role in resting lymphocytes.
Collapse
Affiliation(s)
- Céline Silva Lages
- Laboratoire de RadioPathologie, DRR/DSV, CEA, IPSC, Fontenay-aux-Roses, France
| | | | | | | | | | | | | |
Collapse
|
|
32
|
Guilleret I, Benhattar J. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Exp Cell Res 2003; 289:326-34. [PMID: 14499633 DOI: 10.1016/s0014-4827(03)00281-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Telomerase is the ribonucleoproteic complex involved in maintaining telomere size. It is expressed in germ and stem cells but not in normal somatic cells. In most tumors, telomerase is reactivated. In humans, telomerase activity is tightly regulated by expression of the hTERT gene. In a previous study, we found a direct correlation between methylation of the hTERT promoter and hTERT gene expression. In order to demonstrate this correlation, demethylation experiments were performed with the demethylating agent 5aza-2'-deoxycytidine (5azadC). Three telomerase-positive tumor cell lines (Lan-1, HeLa, and Co115), presenting a hypermethylated hTERT promoter, were treated with different doses and types of treatment for a long period. Analysis of methylation revealed a final hTERT promoter demethylation up to 95%. Quantification of hTERT mRNA showed that transcription was strongly repressed during drug exposure. In contrast, expression of c-Myc, an activator of hTERT promoter, was barely down-regulated or increased by the treatment. Using a TRAP assay, telomerase activity was semiquantified in all experiments. It strongly decreased or was suppressed after two to four passages. Finally, telomere length was measured by Southern blot. Their averages were not modified, but ranges concentrated around the mean. Thus, it is likely that hTERT promoter hypermethylation would be necessary for its expression.
Collapse
MESH Headings
- Antimetabolites, Antineoplastic/pharmacology
- Azacitidine/analogs & derivatives
- Azacitidine/pharmacology
- Cell Division/drug effects
- Cell Division/genetics
- Cellular Senescence/drug effects
- Cellular Senescence/genetics
- DNA Methylation/drug effects
- DNA-Binding Proteins
- Decitabine
- Down-Regulation/drug effects
- Down-Regulation/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Neoplasms/enzymology
- Neoplasms/genetics
- Promoter Regions, Genetic/drug effects
- Promoter Regions, Genetic/genetics
- Proto-Oncogene Proteins c-myc/drug effects
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Telomerase/drug effects
- Telomerase/genetics
- Telomerase/metabolism
- Telomere/drug effects
- Telomere/genetics
- Telomere/metabolism
- Transcription, Genetic/drug effects
- Transcription, Genetic/genetics
- Tumor Cells, Cultured
Collapse
Affiliation(s)
- Isabelle Guilleret
- Institut de Pathologie, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland
| | | |
Collapse
|
|
33
|
Abstract
Canine and feline lymphoma is a common hematopoietic malignancy that generally responds well to systemic chemotherapy. In dogs, several recent investigations have underscored the beneficial effects of adjunctive radiation therapy for the treatment of multicentric lymphoma. With the emergence of effective immunotherapeutic agents against non-Hodgkin's lymphoma in people, some of these specific targeted immunotherapeutics may soon be a viable option for treating lymphoid malignancies in dogs. Although the effective and durable treatment of feline lymphoma remains disappointing, the identification of environmental etiologic factors may help to shape future recommendations for disease prevention. It is only reasonable to assume that as our fundamental understanding of lymphoid malignancies grows, better diagnostic tools, predictive markers, and therapeutic options will also emerge.
Collapse
Affiliation(s)
- Timothy M Fan
- Department of Veterinary Clinical Medicine, Veterinary Teaching Hospital, College of Veterinary Medicine, University of Illinois, 100 West Hazelwood Drive, Urbana, IL 61802, USA.
| |
Collapse
|
|
34
|
Walter M, Davies JP, Ioannou YA. Telomerase immortalization upregulates Rab9 expression and restores LDL cholesterol egress from Niemann-Pick C1 late endosomes. J Lipid Res 2003; 44:243-53. [PMID: 12576506 DOI: 10.1194/jlr.m200230-jlr200] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Niemann-Pick C (NPC) disease is a rare recessive lipidosis marked by excessive accumulation of LDL-derived free cholesterol and glycosphingolipids in the late endosomal-lysosomal (E-L) system. Here we report that ectopic expression of human telomerase reverse transcriptase (hTeRT) in human cells leads to an upregulation of the small GTPase Rab9 and its effector p40. Expression of hTeRT in NPC1 cells results in a correction of their cellular phenotype, including clearance of accumulated cholesterol from their E-L system. Specifically, in NPC1-TeRT cells, the transport of cholesterol from the E-L system to the plasma membrane is restored with a concomitant increase in cholesterol esterification. This effect is Rab9-specific since expression of Rab9 in untransformed NPC1 cells also leads to a reversal of their disease phenotype. These effects are also seen in normal TeRT-immortalized cells and it appears that TeRT expression leads to an increase in the transport of molecules, including cholesterol, from the E-L system, and may play a role in increasing cellular proliferation. These results suggest the existence of alternative endogenous therapeutic targets that can be modulated to reverse the NPC1 disease phenotype.
Collapse
Affiliation(s)
- Marc Walter
- Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
| | | | | |
Collapse
|
|
35
|
Reith A, Sudbø J. Impact of genomic instability in risk assessment and chemoprevention of oral premalignancies. Int J Cancer 2002; 101:205-9. [PMID: 12209969 DOI: 10.1002/ijc.10569] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Head-and-neck cancer is a disfiguring disease with increasing incidence rates even in young people, whose exposure to known risk factors is limited. This emphasizes the importance of early identification, on an individual basis, of precursor lesions that will develop into carcinomas. The clinical value of identifying individuals at high risk of oral cancer is emphasized by the fact that these patients are likely to benefit from available chemopreventive measures, largely without adverse effects.
Collapse
Affiliation(s)
- Albrecht Reith
- Department of Pathology, Norwegian Radium Hospital, University of Oslo, Norway
| | | |
Collapse
|