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Keywords:

  • telomerase;
  • hTERT;
  • lung cancer;
  • preneoplasia

Abstract

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

Telomeres are specialized structures at eukaryotic chromosomes ends, which role is to prevent them from degradation, end to-end fusion and rearrangement. However, they shorten after each cellular division because of an incomplete DNA replication, acting in normal somatic cells as a mitotic clock for permanent proliferation arrest or senescence entry. Short telomeres are perceived as damaged DNA leading to p53/ATM pathway activation. In tumoral cells, a ribonucleoprotein complex termed telomerase enables telomere elongation. This complex, composed of 2 main components, the telomerase RNA component or hTR, the RNA template for telomere synthesis, and telomerase reverse transcriptase, the catalytic subunit, is reactivated in the majority of cancers, including those of the lung. In this review, we briefly present the main results on telomerase expression in various histological types of lung carcinoma and in bronchial carcinogenesis along with telomere attrition. Inhibition of one of the main components of the enzyme or limitation of telomere access by telomerase represent novel targets for cancer therapies and chemoprevention in high risk patients of lung cancer. © 2007 Wiley-Liss, Inc.

Telomeres are nucleoprotein complexes located at the end of eukaryotic chromosomes, and are composed of double stranded TTAGGG repeats with a 3′ single strand overhang or G tail. They protect chromosome ends from exonucleolytic degradation, end-to end fusion and chromosomal rearrangements, and are associated with various binding proteins favoring telomere capping and chromosome end stabilization. Telomere lengths differ among mammals; human telomeres are 5–15 kb long, while those of mice may exceed 60 kb. As DNA polymerase cannot fully replicate ends of linear DNA complexes, telomeres shorten with each cell division, with a loss of 50–200 base pairs per round of DNA replication. Hence, growth and division result in progressive telomere erosion, and critically shortened telomeres are recognized as double strand breaks, which trigger DNA damage responses. Telomeres can form a duplex loop structure (referred as the T-loop), in which the single-stranded 3′ end folds into the duplex telomeric tract to form a D-loop.1 Conformation in a closed (folded) state prevents activation of DNA damage responses and limits the telomere access to an enzyme, telomerase, responsible for telomere elongation.2, 3 Telomere looping or folding depends on the presence of telomere binding and telomere associated proteins, such as TRF-1 and TRF-2, TIN-2, PINX-1, Tankyrase 1, Rap1 and Pot1.4–7 Telomeric DNA also forms quadruplex intramolecular or intermolecular structures through guanine tetrads, implicating either 2 double-stranded or 4 single-stranded telomeric DNAs. These G quadruplex structures, which formation is favored by folding proteins such as Rap-1 and topoisomerase 1, are essential for telomere capping and may influence transcription of genes such as c-Myc.8

Telomere impairment, caused either by capping deficiency or critical shortening, limits cell proliferation via induction of apoptosis or senescence.9, 10 Senescence represents a state in which cells can no longer proliferate but remain viable. This form of terminal differentiation is not only induced by DNA damage (like oxidative stress) and oncogenes activation, but also by alterations of length and structure of telomeres. Senescence requires activation of P53 or Rb proteins and their regulators, such as P16INK4a, P21 and P14ARF. Senescence induced by P53 is mediated by P21 activation, a cyclin-dependent kinase inhibitor (CDKI). P21 inhibits cyclin-dependent kinases, prevents phosphorylation and inactivation of Rb and related proteins P107 and P130.11 P14ARF binds human double minute protein 2 (HDM2) and thus inhibits P53 degradation triggered by HDM2.12 Another CDKI, P16INK4a is implicated in senescence through Rb hypophosphorylation and is induced by MAP kinase signaling.13

In absence of adequate sized telomeres, normal somatic cells undergo replicative senescence, also called Hayflick limit or cellular mortality stage 1 (M1),14, 15 and short telomeres, perceived as damaged DNA, induce p53/ataxia telangiectasia mutated (ATM) kinase pathway activation.16, 17 Senescence phenotype induced by telomere dysfunction includes nuclear accumulation of phosphorylated ATM, phosphorylated histone H2AX, p53 binding protein 53BP1, NBS1- or phosphoS966 form of SMC1, MDC1 and activation of CHK1 and CHK2 checkpoint kinases.18 In contrast, tumor cells lacking P53 and Rb mediated checkpoints, can escape mortality stage 1, and proliferate until they reach mortality stage 2 (M2), or “crisis”, where they suffer huge genetic instability.19 At this stage, telomeric dysfunction, which leads to breakage-fusion-bridge cycles, formation of dicentric or ring chromosomes and massive cell death, allows in turn new genetic abnormalities to take place in a subpopulation of surviving cells, which assumes tumor progression.19–21 Telomere shortening is thus endowed with tumor suppressor function in actively dividing cells, acting as a “mitotic clock” in somatic cells, blocking cell division after a long-term proliferation either by apoptosis or senescence via P53/Rb pathway activation. Alternatively, telomere erosion contributes to tumorigenesis in a context of loss of P53 functions, as inferred from mice mTerc−/− p53−/− with short telomeres and a high genomic instability, which are highly subjected to breast, colon and skin carcinoma development.20, 22, 23 These data built a conceptual model of immortalization and tumoral proliferation. This review will focus on the data acquired in lung cancer, which fit and built the model. It is well known that oncogenic stimuli at the earliest stages of carcinogenesis favor cell proliferation and DNA replication, which increase genomic instability and exert a pressure of selection for P53 mutations. Concomitantly, telomere attrition caused by cell proliferation, results in DNA damage response, and preinvasive lesions exhibit high levels of phosphorylated CHK2, ATM, H2AX and P53 proteins24, 25 At a more advanced stage, dysplastic cells endow ATM/ CHK2/p53 pathway mutations, and either survive crisis by telomerase reactivation or die.26 This scheme could explain the 2 scenarios of regression of a subset of preneoplastic bronchial lesions27 and progression to high- grade lesions of others (Fig. 1). It is to be noted that an alternative lengthening of telomeres (ALT) is observed in 10–15% of telomerase negative tumors, mainly osteosarcoma and adrenal carcinoma, in which tumor cells exhibit long telomeres via homologous recombination.28

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Figure 1. Scheme of a possible explanation for regression or progression of preneoplastic bronchial lesions. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Telomerase: structure and regulation

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

First characterized in Tetrahymena thermophila, telomerase extends the lagging strand in 5′ after incomplete replication by conventional DNA polymerases, and enables de novo synthesis and maintenance of telomere repeats. This ribonucleoprotein complex is composed of 2 major components: a 451 nucleotide RNA, the telomerase RNA component (hTERC), which serves as a template for addition of repeated TTAGGG sequences onto chromosome ends; and a 127 kDa protein, or catalytic component telomerase reverse transcriptase (hTERT) with reverse transcriptase properties.29, 30 Human TERC belongs to the family of small nucleolar RNAs and contains a H/ACA domain, essential for telomerase activity, hTERC nuclear accumulation and maturation in 3′.31 Whereas hTERC expression is broader in distribution, hTERT expression is classically very low or absent in most human somatic tissues, and physiologically restricted to germ and stem cells and activated lymphocytes,32, 33 leading to consider hTERT as the limited factor for telomerase activity. Exogeneous telomerase expression results in telomere maintenance or elongation in normal somatic cells and participates to cell immortalization in some cases.34 Action of telomerase is transient and cell cycle restricted, induced by a telomere structure switch.35

Mechanisms of telomerase re-expression during carcinogenesis are not yet completely understood. HTERT gene amplifications are observed in nearly one third of human tumors, in relation to an increase of gene copy number, an aneusomy, or gains in 5p.36 Moreover, numerous putative positive and negative regulators have been reported at the transcriptional level. For instance, hTERT promoter is activated by c-Myc, and its transfection induces hTERT mRNA accumulation in human cultured fibroblasts.37 HTERT promoter contains E box binding sites for Myc/Max or Mad/Max dimeres, and overexpression of Mad-1 suppresses hTERT expression.38 HTERT promoter is also activated by SP1,39 E6 protein of human papilloma virus 16, estrogen and androgen. Negative regulators include wild type P53, Rb and E2F, individually or in a repressive complex,40, 41 in addition to WT1, interferon alpha and transforming growth factor beta (TGFβ).42 Human TERT gene promoter is located in a CpG island, but the extend of methylation does not seem to correlate with telomerase expression and regulation. Although demethylation by 5-azacytidine induces telomerase expression, suggesting that hTERT gene promoter hyper methylation negatively regulates telomerase expression,43, 44 demethylation was also reported to reduce telomerase expression and to shorten telomeres.45 In addition, CpG islands may be unmethylated in telomerase negative or positive cells suggesting other mechanisms of telomerase regulation. Whereas only the full-length hTERT protein is catalytically active and associated with telomerase activity, alternative splicing through synthesis of truncated dysfunctional proteins from other spliced variants, participates to telomerase regulation during embryonal development and in malignancies.46 Other mechanisms of regulation include post- translational modifications, such as hTERT phosphorylation by protein kinase C (PKC), protein kinase 2A (PKA), protein kinase B (PKB/Akt)47–49 and sub cellular delocalization at the protein level (nucleoplasmic rather than nucleolar).50, 51

Telomerase enables immortalization and telomere structure stabilization in lung cancer

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

Telomerase mRNA expression and or telomerase activity have been widely reported in up to 85% of human cancers, and a telomerase activity has been demonstrated in small cell lung carcinomas (SCLC) and nonsmall cell lung carcinomas (NSCLC) including neuroendocrine tumors, adenocarcinomas and their precursor lesion (namely atypical alveolar hyperplasia) as well as in pulmonary sarcomas and mesotheliomas.52–58 Almost all small-cell lung carcinoma and the vast majority of non small-cell lung carcinoma display a substantial telomerase activity in 62–96% of the cases (Table I).54, 56, 59 According to the literature, 60–91% of squamous carcinomas and 67–100% of large cell carcinoma display a telomerase activity as assessed by telomeric repeat assay protocol (TRAP) assay. Adenocarcinomas are telomerase positive in 69–92%, except bronchioloalveolar carcinoma, which are telomerase positive in only 40% of the cases.52, 56, 59–61 Several reports have suggested that high levels of telomerase activity or hTERT mRNA levels are correlated with a poor survival in stage I NSCLC,61–63 with tumor recurrence, histological type, grade52, 61, 62 or smoking status.64

Table I. Relative Telomerase Activity Measured by TRAP Assay, According to Lung Cancer Histology
 SCCAdenocarcinomaLarge cell carcinomaCarcinoidsLCNECSCLC
  • SCC, squamous cell carcinoma; BAC, bronchioloalveolar carcinoma; LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung carcinoma.

  • 1

    No. of positive cases/no. of cases studied.

  • 2

    Values in parenthesis indicate percentages.

Albanell et al., 19975930/361 (83.3)248/56 (85.7)6/7 (85.7)   
Fujiwara et al., 200060 22/25 (92)    
Hiyama et al., 19955646/52 (88.5)45/65 (69)    
Kumaki et al., 20015241/45 (91.1)50/54 (92.6)12/12 (100)   
Marchetti et al., 19966134/57 (60)24/34 (71); BAC: 4/10 (40)4/6 (67)   
Zaffaroni et al., 200368   1/15 (7)7/8 (87)14/15 (93)
Zaffaroni et al., 200569   5/24 (20)8/12 (66)14/16 (87)

SCLC are telomerase positive in nearly 90–100% of the cases, with very high levels of enzyme activity,56, 65 and thus conform to the model of a high proliferation with extensive genetic instability, as demonstrated by their numerous allelic losses in 3p, 13q14, 5q21 and 17q13, and evasion from p53/Rb functions and cell cycle checkpoints with P14 loss. Most of them, at the time of diagnosis, have undergone a high number of cell divisions, and can continue to divide themselves thanks to telomerase re-expression, being mainly composed of post M2 immortal cells highly telomerase positive. Conversely, NSCLC are partly composed of pre-mortal cells telomerase negative but with long telomeres, and partly of post-mortal cells, which became immortal because of telomerase reactivation.56

We have previously analyzed telomerase reactivation by using the following techniques: (i) immunohistochemistry, (ii) telomerase activity measurement by TRAP assay, (iii) in situ hybridization, summarized in Table II as well as telomere length analysis. We have demonstrated that telomerase expression varies significantly according to histological type of lung tumors65 (Fig. 2), and we have found in agreement with the literature56, 60, 61 that adenocarcinoma displayed the lowest level of telomerase activity, particularly in the bronchioloalveolar component, in contrast with basaloid carcinoma, an aggressive lung tumor, which exhibits similar high levels of telomerase expression to small-cell lung carcinoma. We have also reported that hTERT can preferentially locate onto nucleolar structures in 45% of squamous cell carcinoma and 42% of adenocarcinomas, in contrast with its diffuse nuclear localization in all small-cell lung carcinoma and 74% of basaloid carcinoma. A shorter survival in stage I NSCLC was correlated with a nucleolar pattern of staining. However, after publication of these studies, it has been recently demonstrated unambiguously that the NCL-hTERT (Novocastra) antibody used in fact recognized nucleolin rather than telomerase, leading us to a reappraisal of our findings in the sense that expression and sublocalization of nucleolin is actually associated with prognosis and clinicopathological characteristics of cancer. Indeed, Wu et al.66 showed that the protein recognized by NCL-hTERT antibody was still present in telomerase negative GM847 cell lines, and exhibited on western blotting analysis and on two-dimensional gel electropheresis respectively the same molecular weight of 100 kDa and the same isoelectrical point than nucleolin and colocalized with nucleolin using confocal microscopy and immunofluorescence. Moreover, they demonstrated that 2 proteins are in fact recognized by this antibody, nucleolin and alpha actinin 1 and 4 on the basis of mass spectrometry microsequencing, and could not correspond to related or truncated hTERT. Interestingly, they also showed that nucleolin co-immunprecipitates with hTERT, and is degradaded during apoptosis and downregulated during differentiation; Of note, nucleolar localization of hTERT naturally occurs during telomerase complex assembly to favor hTERC maturation and complex stabilization, but also seems to correspond to a sequestration of hTERT away from its telomeric targets during S phase or repair of DNA breaks, independently of hTERC binding.50, 51 Conversely, in SV 40 transfected cells, hTERT is released into the nucleoplasmic compartment where the telomeric sequence synthesis takes place.51 As it has been shown that nucleolin and hTERT follow the same subcellular localization,67 we now suggest to explain the unfavorable prognostic influence of nucleolar localized nucleolin in stage I NSCLC, that nucleolar nucleolin accumulation is correlated with a state of hiatus of differentiation and high proliferation in keeping with a poor prognosis. In contrast, concomitant nucleolar and nuclear distribution of nucleolin probably linked to hTERT, observed in high-grade tumors such as small cell lung carcinoma and basaloid carcinoma, is compatible with a strong and aberrant increase of nucleolin accumulation and maybe of telomerase activation in tumors that have reached a high level of genetic lesions and escape senescence and apoptosis. These might represent post M2 cell population.

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Figure 2. Telomerase expression assessed by in situ hybridization in pulmonary carcinomas. (a) Papillary pulmonary adenocarcinoma showing a mild cytoplasmic staining (×200). (b) Squamous cell carcinoma exhibiting a cytoplasmic staining with a moderate intensity (×200). (c,d) Basaloid carcinoma and small-cell lung carcinoma presenting with a strong and diffuse cytoplasmic staining (×200). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Table II. Principal Methods for Telomerase Expression and Telomere Length Analysis
ObjectivesMethodsAdvantages/Disadvantages
Telomerase activity measurementTRAP assays (standard, fluorescent, nonradioactive ELISA-based assay)Direct evaluation of telomerase activity, semiquantitative approach/high amount of fresh cells required, RNAse free conditions, no evaluation of cellular heterogeneity and tissular distribution
Telomere in situ detectionTelomere FISH (peptide nucleic acid probes)Available on routine fixed tissues, with a good appreciation of cellular heterogeneity/quantification
Analysis of RNA components: hTERC or hTERT mRNA expressionRT-PCR (classical or quantitative)Suited for a small amount of cells, good correlation with telomerase activity/no evaluation of cellular heterogeneity and tissular distribution, RNA preservation and RNAses contamination
In situ expression of hTERC or hTERT mRNAIn situ hybridizationIn situ assessment of marker expression, evaluates heterogeneity of distribution on routine fixed tissues, good correlation with telomerase activity (for hTERT)/RNA preservation and RNAses contamination
In situ expression of hTERT proteinImmunohistochemistryIn situ assessment of marker expression, evaluates heterogeneity of distribution on routine fixed tissues, good correlation with telomerase activity/specificity of commercial antibodies

High-grade neuroendocrine lung tumors, including small cell lung carcinoma and large cell neuroendocrine carcinoma, also exhibit high levels of telomerase activity.68 This is in contrast with typical carcinoids, where lack of telomerase is associated with long telomeres.69 Telomerase expression is correlated with P53, BCL2 and c-kit in addition to loss of Rb expression.68

Telomerase activation in preneoplastic bronchial lesions contributes to cancer development

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

An early telomerase re-expression (mRNA and activity) has been reported during oral carcinogenesis, in in situ carcinoma of the breast and in cervical intraepithelial neoplasia (CIN) grade III,70–72 and high levels of hTERT mRNA have been observed by Nakanishi et al.55 in 77% of high-grade atypical alveolar hyperplasia (AAH), 97% of nonmucinous bronchioloalveolar carcinoma but in only 27% of low grade AAH. In preneoplastic bronchial lesions, elevated hTERC levels were detected as early as squamous metaplasia,57 and focally observed in in situ carcinoma in close vicinity with invasive process. We and others have demonstrated that hTERT mRNA significantly increased in preneoplastic lesions along with the severity of their grade,57, 73–75 and interestingly, we have showed that lenghtening of telomeres was concomitant (Fig. 2). Indeed, telomere shortening represents an early event in carcinogenesis, occurring in prostate and pancreatic carcinogenesis at the level of intraepithelial neoplasia.76 Using an in situ hybridization technique for telomere length assessment, a dramatic telomeric signal decrease occurs as early as squamous metaplasia, preceding telomerase re- expression in dysplasia.75 However, the predictive value of telomere shortening for occurrence of lung cancer in high-risk patients with pre-neoplastic lesions remains to be assessed using logistic regression analysis of larger series. Along the same lines, the relationship between telomere attrition and genetic instability in bronchial precancereous lesions also needs to be further analyzed, as well as telomerase expression using mRNA in situ hybridization or specific antibodies raised against hTERT other than NCL-hTERT.

Telomere length in lung cancer

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

Telomere length could represent a prognostic factor in nonsmall cell lung carcinoma, reflecting indirectly chromosomal instability. Telomere length measurement methods include mainly southern blot, fluorescence in situ hybridization and telomere DNA content (TC) titration assay.77, 78 However, within a same population of tumor cells or at the level of each cell, telomere lengths are highly variable, depending on the balance of telomere shortening and telomere elongation by telomerase, so that no direct correlation is observed between telomere length and telomerase activity at the level of individual tumor cells. Overall, telomere lengths are shorter in tumor cells than in normal cells, although some tumors, such as basal carcinoma of the skin or renal cell carcinoma, can harbor longer telomere than normal.79 In lung cancers, only a few reports have documented the possible role of telomere length as prognostic factor. Hirashima et al.80 have shown that nearly 35% of stage I-III NSCLC patients with alteration in terminal restriction fragment (TRF) length, i.e TRF shorter than 4.0 Kb or longer than 8.4 Kb, had shorter survival.

Telomeres and telomerase as targets for anti cancer strategy development

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

Telomerase and telomeric complex play a key role in lung tumor progression. As telomere maintenance is essential to tumor cell proliferation, several approaches have been developed to target either telomerase or telomeric complex. Anti telomerase strategies can either target hTERT or hTERC, in addition to modulation of telomerase regulators at the transcriptional and post-transcriptional levels. More recently, the use of specific ligands leading to G quadruplex telomeric structure stabilization and therefore to limitation of telomerase accessibility to its target appears as a promising area of development.81 A subset of them have been investigated in vitro on lung cancer cell lines; for instance, nonnucleosidic inhibitors such as TMP1, an isiothiazolone derivative, the rhodocyanine FJ5002 and the BIBR, which all bind the reverse transcriptase site of hTERT, inhibit telomerase activity and lead to telomere attrition.82–84 In the same way, antisense molecules, i.e. DNA, PNA, siRNA and ribozymes targeting hTERT mRNA, were used in a subset of cancer cells lines to block or degrade complementary antisense RNA, and siRNA were shown to transiently inhibit telomerase activity in lung cancer cell lines, although more demonstrative in hepatocelular carcinoma cell lines.85, 86 GRN163L, a lipid-modified oligonucleotide complementary to the telomerase RNA, inhibits telomerase activity in A549 lung cancer cell line. It induces progressive telomere shortening and prevents from development of visceral metastases.87 Anti hTERC drugs tested in lung cancer cell lines included mutated polypeptides deletion spliced mRNA isoforms, named DN-hTERT and hTERT alpha, and are responsible for hTERC sequestration. An ectopic expression of DN-hTERT results in inhibition of telomerase activity and reduction of telomere length in A549 lung cancer cell line.88 Telomerase cofactors such as antibiotics, 3PI-kinase inhibitors, PKC inhibitors causing hTERT or cofactor dephosphorylation, also decrease telomerase activity in cancer cell lines from the breast, lung and kidney, while G quartet interactive ligands, such as BRACO 19, quinoline triazines, 2-6 pyridine dicarboxamides, and telomestatin, which bind to telomeric DNA and alter telomere integrity, were shown to induce telomerase down-regulation and telomere instability.89, 90

Telomerase inhibitors should have their greatest impact in combination with cytotoxic chemotherapy in advanced-stage disease, as they may be predominantly effective after multiple cell divisions to cause cell death. They could be of interest particularly in high-grade tumours such as BC and SCLC, and in adjuvant therapy to surgery in early stage disease. In addition, these promising drugs could represent potential chemopreventive agents in high-risk patients such as heavy smokers presenting preinvasive telomerase positive lesions with short telomeres.

Conclusion

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References

Telomerase reexpression is a key factor in cancer cells biology, enabling malignant cells to proliferate indefinitely. Telomerase stabilizes telomere structures in established tumors, but also contributes to cancer development at the early stages of tumorogenesis. While telomere attrition acts as a tumor suppressor by triggering replicative senescence in cells with normal DNA damage responses and P53/Rb pathways, telomerase stabilizes abnormal short telomeres and allows proliferation of tumor cells with acquired mutations resulting in P53/Rb pathway inactivation, and thus promotes malignant transformation. However, further analyses are required to better investigate the pathway of the response to telomere shortening induced- DNA damage and to catch the failure mechanisms of this response. This implies to precise the respective role of telomere- associated proteins involved in DNA damage response and in the regulation of telomere accessibility for telomerase. A better comprehension of the telomere elongation machinery and the role of telomerase in tumors and preneoplasia are essential for development of anti-telomerase therapies, which should be specifically adapted to the tumor histology and phenotype. New tools for telomerase protein measurement appraisal should be developed that do not react or cross react with nucleolin.

References

  1. Top of page
  2. Abstract
  3. Telomerase: structure and regulation
  4. Telomerase enables immortalization and telomere structure stabilization in lung cancer
  5. Telomerase activation in preneoplastic bronchial lesions contributes to cancer development
  6. Telomere length in lung cancer
  7. Telomeres and telomerase as targets for anti cancer strategy development
  8. Conclusion
  9. References
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