Cancer telomerase

Telomeres and cancer. Telomerase is not active in most human cells. Some cancer biologists have suggested that activation of the telomerase gene would be a requirement for a cell to become cancerous. Explain why this might be the case. 

Pharmexa s Telovax is a telomerase peptide vaccine for the treatment of locally advanced or metastatic pancreatic cancer. Telomerase is a common tumour antigen overexpressed in most tumour types and, importantly, recent studies suggest that tumour stem cells are also telomerase positive [109]. As telomerase is important in the maintenance of telomeres and replicative immortality, it is expected that tumours cannot develop resistance to telomerase-based therapies. 

ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. 

NAASANI I, SEIMIYA H and TSURUO T (1998) Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins , Biochem Biophys Res Commun, 249 (2), 391-6. 

Hahn WC et al. (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5(10) 1164-1170... 

Chen Z, Koeneman KS, Corey DR (2003) Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. Cancer Res 63(18) 5917-... 

The dicytodendrins A-E (Fig. 9) are one of the most recent 3,4-diarylpyrrole natural products to be reported [64], Their isolation by Fusetani and coworkers from a Japanese marine sponge was reported in 2003. These substances (144-148) have been shown to inhibit telomerase at a concentration of 50 pg/mL thereby making such compounds potentially useful as antitumor agents given that telomerase activity is found in 90% of cancer cells but... 

Zhang Z et al. (2006). Delivery of telomerase reverse transcriptase small interfering RNA in complex with positively charged single-walled carbon nanotubes suppresses tumor growth. Clin. Cancer Res. 12(16) 4933 1939. 

Shammas MA, Reis RJS, Cheng L, Koley H, Hurley LH, Anedrson KC, Munshi NC (2004) Telomerase inhibition and cell growth arrest after telomestatin treatment in multiple myeloma. Chn Cancer Res... 

Cancer ceDs often have relatively h%h levels of telomerase, preventing the telomeres ftom becoming shortened and contributing to the immortality of malignant cells. 

Greider CW. Telomerase activation. One step on the road to cancer Trends Genet. 1999 15 109-112. 

Engelhardt M, Mackenzie K, Drullinsky P, Silver RT, Moore MA. Telomerase activity and telomere length in acute and chronic leukemia, pre and post ex vivo cultiue. Cancer Res. 2000 60 610-617. 

Damm K, Hemmann U, Garin Chesa P et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001 20 6958-6968. 

An enzyme that uses an RNA template to add DNA to the ends of chromosomes. Telomerase is normally active only in stem cells and those cells giving rise to sperm and egg, but telomerase also undergoes activation when cells become cancerous. In the latter case, telomerase action allows transformed cells to replicate without a limit, a process termed immortalization . 

In the laboratory the immortal cell lines are those derived from cancer. The most famous is the HeLa cancer cells that many of us use as one of the cell lines tested against various anticancer agents. The name HeLa cells is derived from Henrietta Lacks, a black woman, who died from cervical cancer. The cells are so strong that they invade other cell lines, both healthy and other cancer cell lines, giving contaminated or mutated cell lines. HeLa cells have good telomerase levels. If antisense RNA is added to HeLa cells so that the RNA contains the opposite message to the ordinary RNA in the telomerase, the effect is that the telomerase is blocked and the HeLa cells are no longer immortal and die after about 25 replications. 

Most human cells have very low telomerase activity, but cancer cells have high telomerase activity, which allows them to avoid senescence and become "immortal."... 

Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells Bums, J.S., Abdallah, B.M., Guldberg, P., Rygaard, J., Schroder, H.D., Kassem, M.(2005). Cancer Res, 15 65 (8) 3126-3135. 

In cells that do not age (for example, germline and cancer cells) the enzyme telomerase replaces the telomeres, thus extending the life of the cell. 

The control of telomerase must be important. The enzyme is active in early embryonic cells and some stem cells. However, most normal cells have little or no telomerase activity and lose telomere length throughout their lifespan with eventual growth arrest.448/454/457 On the other hand, excessive telomerase activity may induce cancer.451/458/459 Certain mutations in the telomerase guide RNA can cause greatly increased telomerase activity.459 The control of telomerase is still poorly understood but involves specific telomere-binding proteins 448,454,460-460b... 

Fuggetta MP, Lanzilli G, Tricarico M, Cottarelli A, Falchetti R, Ravagnan G, Bonmassar E. 2006. Effect of resveratrol on proliferation and telomerase activity of human colon cancer cells in vitro. J Exp Clin Cancer Res 25 189-193. 

Ramachandran C, Fonseca HB, Jhabvala P, Escalon EA, Melnick SJ. 2002. Curcumin inhibits telomerase activity through human telomerase reverse transcritpase in MCF-7 breast cancer cell line. Cancer Lett 184 1-6. 

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