hTERT-based therapy: A universal anticancer approach (Review)

Lü,Mu-Han; Liao,Zhong-Li; Zhao,Xiao-Yan; Fan,Ya-Han; Lin,Xian-Long; Fang,Dian-Chun; Guo,Hong; Yang,Shi-Ming

doi:10.3892/or.2012.2036

hTERT-based therapy: A universal anticancer approach (Review)

Authors:
- Mu-Han Lü
- Zhong-Li Liao
- Xiao-Yan Zhao
- Ya-Han Fan
- Xian-Long Lin
- Dian-Chun Fang
- Hong Guo
- Shi-Ming Yang
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Affiliations: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China, Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: September 17, 2012 https://doi.org/10.3892/or.2012.2036
Pages: 1945-1952

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Abstract

Human telomerase reverse transcriptase (hTERT) has been identiﬁed as a major protein involved in aberrant cell proliferation, immortalization, metastasis and stemness maintenance in a majority of tumors, yet it has little or no expression in normal somatic cells. During the past few years, the development of hTERT-based therapies such as immunotherapy, suicide gene therapy and small-molecule interfering therapy have become critical and specific for eradicating all types of cancer. Here, current knowledge regarding hTERT and its involvement in various cancers and its role as a target of cancer therapies are reviewed. Additionally, hurdles to new cancer therapy development and new therapeutic opportunities are described, along with areas that require further investigation.

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1	Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ and Reddel RR: Protein composition of catalytically active human telomerase from immortal cells. Science. 315:1850–1853. 2007. View Article : Google Scholar : PubMed/NCBI
2	Campisi J, Kim SH, Lim CS and Rubio M: Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol. 36:1619–1637. 2001. View Article : Google Scholar : PubMed/NCBI
3	Zvereva MI, Shcherbakova DM and Dontsova OA: Telomerase: structure, functions, and activity regulation. Biochemistry. 75:1563–1583. 2010.PubMed/NCBI
4	Raptis S and Bapat B: Genetic instability in human tumors. EXS. 303–320. 2006.
5	Lü MH, Deng JQ, Cao YL, Fang DC, Zhang Y and Yang SM: Prognostic role of telomerase activity in gastric adenocarcinoma: a meta-analysis. Exp Ther Med. 3:728–734. 2012.PubMed/NCBI
6	Harley CB: Telomerase and cancer therapeutics. Nat Rev Cancer. 8:167–179. 2008. View Article : Google Scholar
7	Onoda N, Ogisawa K, Ishikawa T, Takenaka C, Tahara H, Inaba M, Takashima T and Hirakawa K: Telomerase activation and expression of its catalytic subunits in benign and malignant tumors of the parathyroid. Surg Today. 34:389–393. 2004. View Article : Google Scholar : PubMed/NCBI
8	Sorbe B, Bohr L, Karlsson L and Bermark B: Combined external and intracavitary irradiation in treatment of advanced cervical carcinomas: predictive factors for local tumor control and early recurrences. Int J Oncol. 36:371–378. 2010.
9	Shay JW and Wright WE: Implications of mapping the human telomerase gene (hTERT) as the most distal gene on chromosome 5p. Neoplasia. 2:195–196. 2000. View Article : Google Scholar : PubMed/NCBI
10	Yu ST, Chen L, Wang HJ, Tang XD, Fang DC and Yang SM: hTERT promotes the invasion of telomerase-negative tumor cells in vitro. Int J Oncol. 35:329–336. 2009.PubMed/NCBI
11	Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, et al: Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 460:66–72. 2009. View Article : Google Scholar : PubMed/NCBI
12	Kanzawa T, Komata T, Kyo S, Germano IM, Kondo Y and Kondo S: Down-regulation of telomerase activity in malignant glioma cells by p27^KIP1. Int J Oncol. 23:1703–1708. 2003.PubMed/NCBI
13	Papanikolaou V, Iliopoulos D, Dimou I, Dubos S, Tsougos I, Theodorou K, Kitsiou-Tzeli S and Tsezou A: The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells. Int J Oncol. 35:1141–1149. 2009.PubMed/NCBI
14	Meeran SM, Patel SN, Chan TH and Tollefsbol TO: A novel prodrug of epigallocatechin-3-gallate: differential epigenetic hTERT repression in human breast cancer cells. Cancer Prev Res. 4:1243–1254. 2011. View Article : Google Scholar : PubMed/NCBI
15	Zhang YF, Tang XD, Gao JH, Fang DC and Yang SM: Heparanase: a universal immunotherapeutic target in human cancers. Drug Discov Today. 16:412–417. 2011. View Article : Google Scholar : PubMed/NCBI
16	Amarnath SM, Dyer CE, Ramesh A, Iwuagwu O, Drew PJ and Greenman J: In vitro quantification of the cytotoxic T lymphocyte response against human telomerase reverse transcriptase in breast cancer. Int J Oncol. 25:211–217. 2004.
17	Titu LV, Loveday RL, Madden LA, Cawkwell L, Monson JR and Greenman J: Cytotoxic T-cell immunity against telomerase reverse transcriptase in colorectal cancer patients. Oncol Rep. 12:871–876. 2004.PubMed/NCBI
18	Naito K, Ueda Y, Itoh T, Fuji N, Shimizu K, Yano Y, Yamamoto Y, Imura K, Kohara J, Iwamoto A, et al: Mature dendritic cells generated from patient-derived peripheral blood monocytes in one-step culture using streptococcal preparation OK-432 exert an enhanced antigen-presenting capacity. Int J Oncol. 28:1481–1489. 2006.
19	Chen L, Liang GP, Tang XD, Chen T, Cai YG, Fang DC, Yu ST, Luo YH and Yang SM: In vitro anti-tumor immune response induced by dendritic cells transfected with hTERT recombinant adenovirus. Biochem Biophys Res Commun. 351:927–934. 2006. View Article : Google Scholar : PubMed/NCBI
20	Su Z, Vieweg J, Weizer AZ, Dahm P, Yancey D, Turaga V, Higgins J, Boczkowski D, Gilboa E and Dannull J: Enhanced induction of telomerase-specific CD4(+) T cells using dendritic cells transfected with RNA encoding a chimeric gene product. Cancer Res. 62:5041–5048. 2002.PubMed/NCBI
21	Chen M, Chen G, Deng S, Liu X, Hutton GJ and Hong J: IFN-beta induces the proliferation of CD4⁺CD25⁺Foxp3⁺ regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis. J Neuroimmunol. 242:39–46. 2012.
22	Liu JP, Chen W, Schwarer AP and Li H: Telomerase in cancer immunotherapy. Biochim Biophys Acta. 1805:35–42. 2010.PubMed/NCBI
23	Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P and Zanetti M: Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc Natl Acad Sci USA. 97:4796–4801. 2000. View Article : Google Scholar : PubMed/NCBI
24	Hernandez J, Garcia-Pons F, Lone YC, Firat H, Schmidt JD, Langlade-Demoyen P and Zanetti M: Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells. Proc Natl Acad Sci USA. 99:12275–12280. 2002. View Article : Google Scholar
25	Scardino A, Gross DA, Alves P, Schultze JL, Graff-Dubois S, Faure O, Tourdot S, Chouaib S, Nadler LM, Lemonnier FA, et al: HER-2/neu and hTERT cryptic epitopes as novel targets for broad spectrum tumor immunotherapy. J Immunol. 168:5900–5906. 2002. View Article : Google Scholar : PubMed/NCBI
26	Thorn M, Wang M, Kloverpris H, Schmidt EG, Fomsgaard A, Wenandy L, Berntsen A, Brunak S, Buus S and Claesson MH: Identification of a new hTERT-derived HLA-A^*0201 restricted, naturally processed CTL epitope. Cancer Immunol Immunother. 56:1755–1763. 2007. View Article : Google Scholar : PubMed/NCBI
27	Schreurs MW, Hermsen MA, Geltink RI, Scholten KB, Brink AA, Kueter EW, Tijssen M, Meijer CJ, Ylstra B, Meijer GA and Hooijberg E: Genomic stability and functional activity may be lost in telomerase-transduced human CD8⁺ T lymphocytes. Blood. 106:2663–2670. 2005. View Article : Google Scholar : PubMed/NCBI
28	Mizukoshi E, Nakamoto Y, Marukawa Y, Arai K, Yamashita T, Tsuji H, Kuzushima K, Takiguchi M and Kaneko S: Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology. 43:1284–1294. 2006. View Article : Google Scholar : PubMed/NCBI
29	Adotevi O, Mollier K, Neuveut C, Cardinaud S, Boulanger E, Mignen B, Fridman WH, Zanetti M, Charneau P, Tartour E, et al: Immunogenic HLA-B^*0702-restricted epitopes derived from human telomerase reverse transcriptase that elicit antitumor cytotoxic T-cell responses. Clin Cancer Res. 12:3158–3167. 2006.PubMed/NCBI
30	Cortez-Gonzalez X, Sidney J, Adotevi O, Sette A, Millard F, Lemonnier F, Langlade-Demoyen P and Zanetti M: Immunogenic HLA-B7-restricted peptides of hTRT. Int Immunol. 18:1707–1718. 2006. View Article : Google Scholar : PubMed/NCBI
31	Bernardeau K, Kerzhero J, Fortun A, Moreau-Aubry A, Favry E, Echasserieau K, Tartour E, Maillere B and Lang F: A simple competitive assay to determine peptide affinity for HLA class II molecules: a useful tool for epitope prediction. J Immunol Methods. 371:97–105. 2011. View Article : Google Scholar : PubMed/NCBI
32	Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G and Gaudernack G: hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother. 60:809–818. 2011. View Article : Google Scholar
33	Wang J, Yu L, Li J, Deng R and Wang X: Characterization of a human telomerase reverse transcriptase sequence containing two antigenic epitopes with high affinity for human leucocyte antigen. Biotechnol Appl Biochem. 48:93–99. 2007. View Article : Google Scholar
34	Vonderheide RH, Anderson KS, Hahn WC, Butler MO, Schultze JL and Nadler LM: Characterization of HLA-A3-restricted cytotoxic T lymphocytes reactive against the widely expressed tumor antigen telomerase. Clin Cancer Res. 7:3343–3348. 2001.PubMed/NCBI
35	Schroers R, Huang XF, Hammer J, Zhang J and Chen SY: Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4⁺ T-helper cells. Cancer Res. 62:2600–2605. 2002.PubMed/NCBI
36	Schroers R, Shen L, Rollins L, Rooney CM, Slawin K, Sonderstrup G, Huang XF and Chen SY: Human telomerase reverse transcriptase-specific T-helper responses induced by promiscuous major histocompatibility complex class II-restricted epitopes. Clin Cancer Res. 9:4743–4755. 2003.
37	Tang XD, Wang GZ, Guo J, Lu MH, Li C, Li N, Chao YL, Li CZ, Wu YY, Hu CJ, Fang DC and Yang SM: Multiple antigenic peptides based on H-2Kb-restricted CTL epitopes from murine heparanase induce a potent antitumor immune response in vivo. Mol Cancer Ther. 11:1183–1192. 2012. View Article : Google Scholar : PubMed/NCBI
38	Parker KC, Bednarek MA and Coligan JE: Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 152:163–175. 1994.PubMed/NCBI
39	Niu BL, Du HM, Shen HP, Lian ZR, Li JZ, Lai X, Wei SD, Zou LQ and Gong JP: Myeloid dendritic cells loaded with dendritic tandem multiple antigenic telomerase reverse transcriptase (hTERT) epitope peptides: a potentially promising tumor vaccine. Vaccine. 30:3395–3404. 2012. View Article : Google Scholar
40	Murofushi Y, Nagano S, Kamizono J, Takahashi T, Fujiwara H, Komiya S, Matsuishi T and Kosai K: Cell cycle-specific changes in hTERT promoter activity in normal and cancerous cells in adenoviral gene therapy: a promising implication of telomerase-dependent targeted cancer gene therapy. Int J Oncol. 29:681–688. 2006.
41	Jacob D, Davis J, Zhu H, Zhang L, Teraishi F, Wu S, Marini FC III and Fang B: Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter. Clin Cancer Res. 10:3535–3541. 2004. View Article : Google Scholar
42	Kyo S and Inoue M: Complex regulatory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene. 21:688–697. 2002. View Article : Google Scholar : PubMed/NCBI
43	Iliopoulos D, Satra M, Drakaki A, Poultsides GA and Tsezou A: Epigenetic regulation of hTERT promoter in hepatocellular carcinomas. Int J Oncol. 34:391–399. 2009.PubMed/NCBI
44	Gu J, Zhang L, Huang X, Lin T, Yin M, Xu K, Ji L, Roth JA and Fang B: A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo. Oncogene. 21:4757–4764. 2002. View Article : Google Scholar : PubMed/NCBI
45	Zhao P, Wang C, Fu Z, You Y, Cheng Y, Lu X, Lu A, Liu N, Pu P, Kang C, Salford LG and Fan X: Lentiviral vector mediated siRNA knock-down of hTERT results in diminished capacity in invasiveness and in vivo growth of human glioma cells in a telomere length-independent manner. Int J Oncol. 31:361–368. 2007.
46	Liu X, Huang H, Wang J, Wang C, Wang M, Zhang B and Pan C: Dendrimers-delivered short hairpin RNA targeting hTERT inhibits oral cancer cell growth in vitro and in vivo. Biochem Pharmacol. 82:17–23. 2011. View Article : Google Scholar : PubMed/NCBI
47	Gandellini P, Folini M, Bandiera R, De Cesare M, Binda M, Veronese S, Daidone MG, Zunino F and Zaffaroni N: Down-regulation of human telomerase reverse transcriptase through specific activation of RNAi pathway quickly results in cancer cell growth impairment. Biochem Pharmacol. 73:1703–1714. 2007. View Article : Google Scholar
48	Kota SK and Balasubramanian S: Cancer therapy via modulation of micro RNA levels: a promising future. Drug Discov Today. 15:733–740. 2010. View Article : Google Scholar : PubMed/NCBI
49	Hao ZM, Luo JY, Cheng J, Li L, He D, Wang QY and Yang GX: Intensive inhibition of hTERT expression by a ribozyme induces rapid apoptosis of cancer cells through a telomere length-independent pathway. Cancer Biol Ther. 4:1098–1103. 2005. View Article : Google Scholar : PubMed/NCBI
50	Sachsinger J, Gonzalez-Suarez E, Samper E, Heicappell R, Muller M and Blasco MA: Telomerase inhibition in RenCa, a murine tumor cell line with short telomeres, by overexpression of a dominant negative mTERT mutant, reveals fundamental differences in telomerase regulation between human and murine cells. Cancer Res. 61:5580–5586. 2001.
51	Cesare AJ and Reddel RR: Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet. 11:319–330. 2010. View Article : Google Scholar : PubMed/NCBI