端粒和端粒酶与肿瘤干细胞的研究现状

目的:总结国内外对端粒、端粒酶与肿瘤起源、肿瘤干细胞的病理研究现状。方法:应用检索MED-LINE及CHKD期刊全文数据库检索系统,以"端粒、端粒酶和肿瘤干细胞"为关键词,检索1997-2008年有关文献。纳入标准:端粒、端粒酶与肿瘤干细胞的论著性文章。根据标准,纳入分析24篇参考文献。结果:端粒酶激活和端粒稳定对肿瘤干细胞演进是必需的,端粒酶激活是肿瘤干细胞自我更新和不定向分化的必要条件,端粒的动力学代表肿瘤干细胞恶性来源和有丝分裂历史,分析肿瘤干细胞端粒长度,端粒酶活性和细胞遗传学特性有助于揭示肿瘤干细胞起源和肿瘤形成历史,从而深化对肿瘤病理的认识,为恶性肿瘤治疗提供依据。结论:端粒和端粒酶在肿瘤干细胞中表达,是消灭肿瘤理想的靶标,有待进一步研究总结。     

Telomeres and telomerase in normal and leukemic hematopoietic cells

Telomere length and telomerase have an important role in normal and malignant hematopoiesis. Telomere erosion can lead to chromosome end fusion and thereby contribute to genomic instability during tumorigenesis. Thus, like complex chromosomal aberrations, telomere length may be a prognostic factor in hematopoietic malignancies. A paper by Sieglova et al. in this issue of Leukemia Research reports on the prognostic impact of telomere shortening in bone marrow (BM) and peripheral blood (PB) specimens of myelodysplastic syndrome (MDS) and MDS converted-AML patients (pts). Their results underline the importance to study telomere biology together with cytogenetics, genomic and proteomic profiling as prognostic factors, in order to improve risk-adapted therapy of MDS and AML pts.     

Telomeres and telomerase in human cancer (review)

Telomerase has recently come into the limelight as one of the most prevalent tumour markers, due to its nearly ubiquitous presence in malignant tissues and absence from most somatic tissues. The essential role of telomeres in unlimited cell proliferation and that of the enzyme in telomere maintenance have suggested that telomerase inhibitors may be effective in cancer therapy. We provide here a compendium and an evaluation of the available data relating to this hypothesis.     

Telomeres, telomerase and oral cancer (Review)

Oral squamous cell carcinoma (oral cancer) and many squamous cell carcinomas of the head and neck arise as a consequence of multiple molecular events induced by the effects of various carcinogens related to tobacco use, environmental factors, and viruses in some instances (e.g., mucosal oncogenic human papillomaviruses), against a background of inheritable resistance or susceptibility. Consequent genetic damage affects many chromosomes and genes, and it is the accumulation of these changes that appears to lead to carcinoma. Telomere maintenance by telomerase or, in its absence, alternative lengthening of telomeres protect this acquired altered genetic information ensuring immortality without losing eukaryotic linear DNA; when this does not occur DNA is lost and end-replication problems arise. Telomerase is reactivated in 80-90% of cancers thus attracting the attention of pathologists and clinicians who have explored its use as a target for anticancer therapy and to develop better diagnostic and prognostic markers. In the last few years, valuable research from various laboratories has provided major insights into telomerase and telomeres leading to their use as diagnostic and prognostic markers in several types of cancer. Moreover, many strategies have emerged which inhibit this complex enzyme for anticancer therapy and are one step ahead of clinical trials. This review explains the basic biology and the clinical implications of telomerase-based diagnosis and prognosis, the prospects for its use in anticancer therapy, and the limitations it presents in the context of oral cancer.     

Telomeres and telomerase in the clinical management of colorectal cancer

Colorectal cancer (CRC) is the third most common cancer worldwide. Our aim is to describe the state of the art about the role of telomeres and telomerase in the clinical management of CRC and its potential utility as prognostic and diagnostic biomarkers and targets of new treatments. Telomere length could be a new diagnostic marker as an anomalous behavior is observed in peripheral blood cells when CRC patients and healthy people are compared. Moreover, telomeres and telomerase may be used as diagnostic markers considering that universal changes appear along the CRC process. Currently, new therapeutic cancer approaches are focused on inhibiting the maintenance of telomere length, choosing as targets telomerase -or its subunits- or the Shelterin complex. The goal of these therapies is the shortening of telomeres and the induction of cell senescence. Telomeres and telomerase emerge as useful molecular tools in the clinical management of CRC.     

Telomeres and telomerase in hematologic neoplasia

Normal hematopoietic cells express telomerase activity, however the presence of telomerase does not necessarily imply stable and thus unchanging telomere length. Gradual telomere loss with aging and rapid cycling of hematopoietic stem cells might contribute to immunosenescence, exhausted hematopoiesis, and increased likelihood of malignant transformation. In leukemias and lymphomas, telomere length may reflect the cellular proliferative history, prior to immortalization. The level of telomerase activity is generally influenced by the fraction of cells in the proliferative pool. Shortened telomeres and high telomerase activity almost always correlates with disease severity in hematologic neoplasias such as relapsed leukemia and high-grade lymphomas, indicating that measurement of telomere length and telomerase activity might be useful to monitor disease condition. Since the mode of action of telomerase inhibitors may require telomeric shortening before induction of apoptosis, anti-telomerase therapy might be helpful for adjuvant therapy following conventional chemotherapy, in vitro purging of neoplastic cells in stem cell transplantation, and treating minimal residual disease. Some promising areas of tissue engineering include rejuvenation of hematopoietic stem cells for improving stem cell transplants or enhancing general immunity for older patients.     

Telomeres and telomerase in normal and malignant B‐cells

The telomeric checkpoint is emerging as a critical sensor of cellular damage, playing a major role in human aging and cancer development. In the meantime, telomere biology is rapidly evolving from a basic discipline to a translational branch, capable of providing major hints for biomarker development, risk assessment and targeted treatment of cancer. These advances have a number of implications in the biology of lymphoid tumours. Moreover, there is considerable interest in the potential role of telomeric dysfunction in the wide array of immunological abnormalities, grouped under the definition of ‘immunosenescence’. This review will summarize the impact of recent advances in telomere biology on the physiology and pathology of the B lymphocyte, with special interest in immunosenescence and lymphomagenesis. Copyright © 2010 John Wiley & Sons, Ltd.     

Telomeres and telomerase in Candida albicans

Telomeres are the nucleoprotein structures at the ends of linear chromosomes and maintain the genomic integrity through multiple cell divisions. Telomeres protect the chromosome ends from degradation, end-to-end fusion and abnormal recombination and they also promote the end replication. The budding yeast Saccharomyces cerevisiae is the most well-studied model system with regard to telomere and telomerase regulation. Recently, the opportunistic fungal pathogen Candida albicans has emerged as an attractive model system for investigating telomere biology. Candida underwent rapid evolutionary divergence with respect to telomere sequences. Concomitant with the evolutionary divergence of telomere sequences, telomere repeat binding factors and telomerase components have also evolved, leading to differences in their functions and domain structures. Thus, the comparative analysis of the telomeres and telomerase-related factors in the budding yeast has provided a better understanding on both conserved and variable aspects of telomere regulation. In this review, I will discuss telomeres and telomerase-related factors and their functions in telomere and telomerase regulation in C. albicans.     

The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines

Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.     

Telomeres, telomerase, and cancer: life on the edge of genomic stability

The presence of telomerase activity in most human tumors, but not in many normal somatic tissues, has raised considerable interest in telomerase as a possible anticancer therapy. Recent advances in the cloning and characterization of mammalian telomerase components have paved the way for a more detailed understanding of the role of telomerase and telomere length maintenance in cell proliferation. Here, we summarize the most recent biochemical and genetic evidence suggesting that telomere length maintenance by telomerase is critical to the proliferative ability of some immortalized mammalian cells in culture and in vivo.     

Role of telomerase in normal and cancer cells.

Shortening of the telomeric DNA at chromosome ends is postulated to limit the lifespan of human cells. In contrast, activation of telomerase, the enzyme that synthesizes telomeric DNA, is proposed to be an essential step in cancer cell immortalization and cancer progression. This review discusses the structure and function of telomeres and telomerase, the role of telomerase in cell immortalization, and the effects of telomerase inactivation on normal and cancer cells. Moreover, data on the experimental use of telomerase assays for cancer detection and diagnosis are reviewed. Finally, the review considers the evidence regarding whether telomerase inhibitors could be used to treat human cancers.     

Lack of telomerase activity in human mesenchymal stem cells.

Telomerase activity and telomere maintenance have been associated with immortality in tumor and embryonic stem cells. Whereas most normal somatic cells are telomerase negative, low levels of this enzyme have been found in adult stem cells from the skin, gut and the hematopoietic system. Here, we show that telomerase activity is not detectable in human mesenchymal stem cells (hMSCs), which have the phenotype SH2+, SH3+, SH4+, CD29+, CD44+, CD14-, CD34- and CD45-, and have the capacity to differentiate into adipocytes, chondrocytes and osteoblasts. These data suggest that hMSCs have a different telomere biology compared to other adult stem cells. Alternatively, true mesenchymal stem cells might be a very rare subpopulation that have a detection level that is below the sensitivity of the TRAP assay.     

胃癌细胞中端粒酶活性的表达研究

Objective To study the relationship between telomerase activity and biological behavior in human gastric cancer cells and appraise the clinical significance of detecting telomerase activity. Methods The telomerase activity in 47 gastric cancer tissue samples, their matched normal tissues, 7 gastric ulcer and 2 gastric cancer cell lines was detected using a PCR-based non-radioisotopic telomeric repeat amplification protocol (TRAP) assay. Results None of the 47 samples from normal gastric tissues expressed telomerase activity. The 41 of 47 cases of gastric cancer presented telomerase activity with an 87.2% positive rate (P<0.001). 2/2 gastric cancer cell lines and 0/7 gastric ulcer line were also positive for telomerase activity. The activity of telomerase was associated with the pathological differentiation of gastric cancer. Conclusion Telomerase activity may be related to the biological behavior of gastric cancer and can help in assessing the malignant potential of gastric cancer. Telomeras activity will be a good diagnostic marker for the detection of gastric cancer.