Telomerase activity and telomere length in the colorectal polyp-carcinoma sequence

Valls, Cristina; Felis, C. Piñol; Espinet, Josep Maria Reñé; García, J Buenestado; Salas, Joan Viñas

doi:10.4321/s1130-01082009000300004

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…Telomere shortening is thought to be an early event in colorectal tumorigenesis, although frequency estimates for adenomas vary widely [10, 16, 17]. Our observations indicate telomere shortening in ~79% of adenomatous polyps >1cm in size.…”

Section: Discussionmentioning

confidence: 68%

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Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

Suraweera

Mouradov

et al. 2016

Oncotarget

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Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.

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Section: Discussionmentioning

confidence: 68%

“…Telomere shortening is considered an early event in colorectal tumorigenesis, with decreased telomere lengths reported in up to 64% of adenomas [10, 16, 17]. …”

Section: Introductionmentioning

confidence: 99%

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

Suraweera

Mouradov

et al. 2016

Oncotarget

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“…The loss of terminal DNA sequences may limit cell life span by two mechanisms: by acting as a mitotic clock and by denuding chromosomes of protective telomeric DNA necessary for cell viability . The same process might occur in vivo . Hastie et al have asked whether there is telomere loss or reduction in common tumors.…”

Section: Cell Senescent Phenotype and Mammalian Telomeres Telomere Rmentioning

confidence: 99%

“…Telomerase activity increases in the colorectal adenoma‐carcinoma sequence, concurrently with a decrease in telomere length. The presence of synchronous cancer modifies telomerase activity in polyps . Telomeric DNA in the skin cells of 21 human subjects aged between 0 and 92 years was quantified by determining the length of the telomeric smear and the relative amount of TTAGGG repeat sequences .…”

Section: Cell Senescent Phenotype and Mammalian Telomeres Telomere Rmentioning

confidence: 99%

Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell‐based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies

Babizhayev

Yegorov

2015

J Biomedical Materials Res

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Accumulated data indicate that wound-care products should have a composition equivalent to that of the skin: a combination of particular growth factors and extracellular matrix (ECM) proteins endogenous to the skin, together with viable epithelial cells, fibroblasts, and mesenchymal stem cells (MSCs). Strategies consisting of bioengineered dressings and cell-based products have emerged for widespread clinical use; however, their performance is not optimal because chronic wounds persist as a serious unmet medical need. Telomerase, the ribonucleoprotein complex that adds telomeric repeats to the ends of chromosomes, is responsible for telomere maintenance, and its expression is associated with cell immortalization and, in certain cases, cancerogenesis. Telomerase contains a catalytic subunit, the telomerase reverse transcriptase (hTERT). Introduction of TERT into human cells extends both their lifespan and their telomeres to lengths typical of young cells. The regulation of TERT involves transcriptional and posttranscriptional molecular biology mechanisms. The manipulation, regulation of telomerase is multifactorial in mammalian cells, involving overall telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Reactive oxygen species (ROS) have been implicated in aging, apoptosis, and necrosis of cells in numerous diseases. Upon production of high levels of ROS from exogenous or endogenous generators, the redox balance is perturbed and cells are shifted into a state of oxidative stress, which subsequently leads to modifications of intracellular proteins and membrane lipid peroxidation and to direct DNA damage. When the oxidative stress is severe, survival of the cell is dependent on the repair or replacement of damaged molecules, which can result in induction of apoptosis in the injured with ROS cells. ROS-mediated oxidative stress induces the depletion of hTERT from the nucleus via export through the nuclear pores. Nuclear export is initiated by ROS-induced phosphorylation of tyrosine 707 within hTERT by the Src kinase family. It might be presumed that protection of mitochondria against oxidative stress is an important telomere length-independent function for telomerase in cell survival. Biotechnology companies are focused on development of therapeutic telomerase vaccines, telomerase inhibitors, and telomerase promoter-driven cell killing in oncology, have a telomerase antagonist in late preclinical studies. Anti-aging medicine-oriented groups have intervened on the market with products working on telomerase activation for a broad range of degenerative diseases in which replicative senescence or telomere dysfunction may play an important role. Since oxidative damage has been shown to shorten telomeres in tissue culture models, the adequate topical, transdermal, or systemic administration of antioxidants (such as, patented ocular administration of 1% N-acetylcarnosine lubricant eye drops in the treatment of cataracts) may be beneficial at preserving telomere lengths a...

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“…Telomerase activity (TA) is the most common molecular marker because of the detection of human neoplasm and can be observed in approximately 85% of all cancer cells, including CRC (6), but not in normal somatic cells (7). Research also shows that TA increases with adenoma-carcinoma sequences (8).…”

mentioning

confidence: 99%

The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis

Xie

Lai

et al. 2016

Balkan Med J

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Background:Recently, accumulated research has found that the expression of telomerase activity (TA) was associated with colorectal cancer (CRC) advancement, whereas the TA prognostic effect in CRC patients is still controversial. Aims: To investigate relationships between TA and CRC clinicopathological parameters. Study Design: Meta-analysis study. Methods:We searched published studies in databases, such as EMBASE, the Cochrane Library, PubMed, and Ovid databases (last search updated to October 2014) by meeting specified search criteria. The quality of the included studies was usually evaluated and a metaanalysis was implemented by Stata 12.0 software. We used an odds ratio (OR) with a 95% confidence interval (CI) to evaluate relationship strengths between TA and CRC clinicopathological parameters. Results: In total, 11 studies (715 patients) were included to assess the relation between TA and metastasis-related parameters in CRC patients. The results indicate that a senior TA expression was connected with the existence of lymph node metastasis (180 patients; OR=2.85, 95% CI=1.40-5.81, p=0.004), and tumor site (522 Colorectal cancer (CRC) is the third most general neoplasm in humans with the CRC mortality rate accounting for around 9% of all tumor deaths (1). The 5-year survival rate of the early stages of CRC after surgical resection is around 85%, while this rate is meaningfully decreased (<50%) in lymph node metastasis positive CRC patients (2). Therefore, early and more accurate detection of tumorigenesis or progression is critical to enhancing therapeutic strategy and prognosis of patients. Accumulating evidence indicates that cellular immortality plays an important role in tumor biology (3).The indispensable and key factor for tumor immortalization and tumorigenesis is telomerase, an enzyme that protects DNA sequences on chromosome ends. Telomerase can prevent cellular senescence in somatic cells through synthesizing

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Telomerase activity and telomere length in the colorectal polyp-carcinoma sequence

Cited by 13 publications

References 20 publications

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell‐based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies

The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis

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