Telomere Dysfunction and DNA Damage Checkpoints in Diseases and Cancer of the Gastrointestinal Tract  K. Lenhard Rudolph, Daniel Hartmann, Oliver G. Opitz  Gastroenterology  Volume 137, Issue 3, Pages 754-762 (September 2009) DOI: 10.1053/j.gastro.2009.07.037 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 The role of telomeres in regeneration and organ maintenance. Aging, chronic disease, life stress, and telomerase mutations can contribute to shortening of telomeres. Telomere shortening leads to an activation of p53-dependent or p53-independent pathways that limit the survival and the function of cells by the induction of senescence, but also apoptosis, or autophagy. The relative contribution of each of these cellular outcomes to impaired tissue maintenance during aging and disease remains to be determined. Gastroenterology 2009 137, 754-762DOI: (10.1053/j.gastro.2009.07.037) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 The role of telomeres and telomerase in carcinogenesis and potential therapeutic targets. Telomere shortening leads to increasing levels of telomere dysfunction in aging or chronically damaged tissues. Telomere dysfunction itself induces chromosomal instability (CIN) and increases the risk of cellular transformation and cancer initiation. The loss of checkpoint functions and environmental alterations (inflammation, cytokine secretion, and ROS, among others) may cooperate with telomere dysfunction to induce CIN and cancer initiation. However, initiated tumor cells need to stabilize telomeres at this stage in order to prevent the evolution of genetic chaos and tumor cell death. This occurs in the vast majority of human cancers, ultimately by activation of telomerase. According to this model, DNA damage checkpoints (senescence and crisis) represent tumor suppressor mechanisms. However, the same checkpoint can contribute to impairment in regenerative reserve and organ maintenance. According to this model telomeres and telomerase could represent therapeutic targets. (i) Telomerase activators could impair the induction of telomere dysfunction, thereby increasing regenerative reserve and preventing the induction of CIN and cancer initiation. As a downside, telomerase activators could promote the progression of telomere dysfunctional, early tumor lesions. (ii) Telomerase inhibitors could impair immortal tumor cell growth and tumor progression. As a downside, the treatment could accelerate telomere shortening in stem cells and the decline in organ maintenance in response to aging and chronic disease. (iii) Checkpoint inhibitors could improve regenerative reserve and organ maintenance in telomere dysfunctional organs. As a downside, this approach could accelerate CIN and tumor formation. Dysfunctional telomeres and signals induced by telomere dysfunction could also represent novel biomarkers indicating the cancer risk and regenerative reserve of organs. Gastroenterology 2009 137, 754-762DOI: (10.1053/j.gastro.2009.07.037) Copyright © 2009 AGA Institute Terms and Conditions