title: The roles of telomerase in the generation of polyploidy during neoplastic cell growth.
abstract: Polyploidy contributes to extensive intratumor genomic heterogeneity that characterizes advanced malignancies and is thought to limit the efficiency of current cancer therapies. It has been shown that telomere deprotection in p53-deficient mouse embryonic fibroblasts leads to high rates of polyploidization. We now show that tumor genome evolution through whole-genome duplication occurs in ∼15% of the karyotyped human neoplasms and correlates with disease progression. In a panel of human cancer and transformed cell lines representing the two known types of genomic instability (chromosomal and microsatellite), as well as the two known pathways of telomere maintenance in cancer (telomerase activity and alternative lengthening of telomeres), telomere dysfunction-driven polyploidization occurred independently of the mutational status of p53. Depending on the preexisting context of telomere maintenance, telomerase activity and its major components, human telomerase reverse transcriptase (hTERT) and human telomerase RNA component (hTERC), exert both reverse transcriptase-related (canonical) and noncanonical functions to affect tumor genome evolution through suppression or induction of polyploidization. These new findings provide a more complete mechanistic understanding of cancer progression that may, in the future, lead to novel therapeutic interventions.
authors: Laboratory of Genetics and Gene Therapy, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors: Agni
authors: A
authors: Christodoulidou
authors: Christina
authors: C
authors: Raftopoulou
authors: Maria
authors: M
authors: Chiourea
authors: George K
authors: GK
authors: Papaioannou
authors: Hirotoshi
authors: H
authors: Hoshiyama
authors: Woodring E
authors: WE
authors: Wright
authors: Jerry W
authors: JW
authors: Shay
authors: Sarantis
authors: S
authors: Gagos
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D058674:Chromosome Duplication / Q000235:genetics; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009154:Mutation; D011123:Polyploidy; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase