Role of telomere dysfunction in genetic intratumor diversity.
ABSTRACT Most solid tumors are unable to maintain the stability of their genomes at the chromosome level. Indeed, cancer cells display highly rearranged karyotypes containing translocations, amplifications, deletions, and gains and losses of whole chromosomes, which reshuffle steadily. This chromosomal instability most likely occurs early in the development of cancer, and may represent an important step in promoting the multiple genetic changes required for the initiation and/or progression of the disease. Different mechanisms may underlie chromosome instability in cancer cells, but a prominent role for telomeres, the tip of linear chromosomes, has been determined. Telomeres are ribonucleoprotein structures that prevent natural chromosome ends being recognized as DNA double-strand breaks, by adopting a loop structure. Loss of telomere function appears from either alteration on telomere-binding proteins or from the progressive telomere shortening that normally occurs under physiological conditions in the majority of cells in tissues. Importantly, unmasked telomeres may either trigger the senescent phenotype that has been linked to the aging process or may initiate the chromosome instability needed for cancer development, depending on the integrity of the DNA damage checkpoint responses. Telomere dysfunction contributes to chromosome instability through end-to-end chromosome fusions entering breakage-fusion-bridge (BFB) cycles. Resolution of chromatin bridge intermediates is likely to contribute greatly to the generation of segmental chromosome amplification events, unbalanced chromosome rearrangements, and whole chromosome aneuploidy. Noteworthy is the fact that telomere length heterogeneity among individuals may directly influence the scrambling of the genome at tumor initiation. However, reiterated BFB cycles would randomly reorganize the cell karyotype, thus increasing the genetic diversity that characterizes tumor cells. Even though a direct link is still lacking, multiple evidence lead one to believe that telomere dysfunction directly contributes to cancer development in humans. The expansion of highly unstable cells due to telomere dysfunction enhances the genetic diversity needed to fuel specific mutations that may promote cell immortalization and the acquisition of a tumor phenotype.
- SourceAvailable from: Alexey Stepanenko
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ABSTRACT: Cancer development is an evolutionary process that has been highly conserved among centuries within organisms. Based on this, the interest in cancer research focuses on cells, organelles and genes that possess a genetic conservatism from yeasts to human. Towards this thought, mitochondria, the highly conserved and responsible for the cellular bioenergetic activity organelles, might play crucial role in carcinogenesis. Interestingly, tumors with low bioenergetic signature have worse prognosis and show a decreased expression of ATPase protein. Furthermore, according to the stem-cell theory of carcinogenesis, aggressive tumors are characterized by an increase number of malignant stem-like cell population and their resistance to chemotherapy has been found to be mitochondrially driven. The above considerations triggered us to hypothesize that mitochondrial bioenergetic processes in stem-like cancer cells plays a crucial role in the highly conserved process of carcinogenesis. Specifically, we support that mitochondrial and/or nuclear DNA alterations that control stem cells' ATP production drive stem cells to "immortalization" (Otto Warburg theory) that mediates cancer initiation and progression. Substantiation of our hypothesis requires evidence that: (1) alterations in mitochondria bioenergetic metabolites and enzymes encoded either from the mtDNA or the nuclear DNA are linked to human cancer and (2) mitochondrial functions are regulated by highly conserved genes involved in cancer-related cellular processes such as apoptosis, aging and autophagy. Experimental approach on how this hypothesis might be tested and promising strategies in cancer therapeutics are also discussed. In case the hypothesis of stem-cell bioenergetic malformations' related carcinogenesis proves to be correct, it would contribute to the development of new prognostic, diagnostic and even more effective therapeutic interventions against various types of cancer.Medical Hypotheses 10/2012; · 1.18 Impact Factor
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ABSTRACT: Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors. We measured peripheral blood leukocyte telomere length at two time points in women enrolled in a multiethnic, prospective cohort of stage I to stage IIIA breast cancer survivors diagnosed between 1995 and 1999 with a median follow-up of 11.2 years. We evaluated associations between telomere length measured at mean 6 (baseline; LTL0; n = 611) and 30 months (LTL30; n = 478) after diagnosis and the change between those time points (n = 478), with breast cancer-specific and all-cause mortality using Cox proportional hazards models adjusted for possible confounders. Statistical tests were two-sided. There were 135 deaths, of which 74 were due to breast cancer. Neither baseline nor 30-month telomere length was associated with either all-cause or breast cancer-specific mortality (LTL0: hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.67 to 1.02; HR = 0.88; 95% CI = 0.67 to 1.15; LTL30: HR = 0.78, 95% CI = 0.59 to 1.05; HR = 0.86; 95% = CI = 0.58 to 1.26, respectively). However, participants whose telomeres shortened between baseline and 30 months were at a statistically significantly increased risk of breast cancer-specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39) compared with participants whose telomeres lengthened. When follow-up was censored at 5-years after diagnosis, LTL0 (HR = 0.66; 95% CI = 0.45 to 0.96), LTL30 (HR = 0.51; 95% CI = 0.29 to 0.92), and change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) were statistically significantly associated with all-cause mortality. Telomere shortening was associated with increased risk of breast cancer-specific and all-cause mortality, suggesting that change in blood telomere length over time could be a biomarker of prognosis. Research on determinants of telomere length and change is needed.CancerSpectrum Knowledge Environment 03/2014; · 14.07 Impact Factor