Molecular Mechanisms of Tumor Initiation in Response to Telomere Shortening

The main function of telomeres is to cap chromosomal ends and to stabilize chromosomes (McEachern et al. 2000). Specifically, telomere capping is necessary to distinguish the chromosome ends from DNA breaks within the genome. While DNA breaks induce checkpoint responses and DNA repair of broken ends, the natural ends of the chromosome should not provoke such responses. Thus, telomere capping prevents the inappropriate activation of DNA repair pathways and the induction of chromosomal fusion. For capping function, telomeres need to have a minimum length and, in addition, need to form three-dimensional structures (e.g., telomere loops, g-quadruplexes) that are stabilized by specific telomere-binding proteins (de Lange 2004; see also Blasco, this volume; Dillin and Karlseder, this volume; Chang, this volume).

Most human cancers that evolve during ageing and at the end stage of chronic diseases are associated with high rates of chromosomal instability (CIN). A current concept in molecular oncology indicates that CIN induces genetic lesions that promote the step-wise progression of altered cells to transform into cancer cells (Michor et al. 2005). Since telomere shortening is associated with an increased cancer risk during ageing and chronic disease, it is conceivable that loss of telomere capping function contributes to the induction of chromosomal instability and cancer initiation (Fig. 11.2). In agreement with this assumption, telomere shortening in humans correlates with the evolution of CIN in chronic diseases associated with an increased cancer risk, e.g., ulcerative colitis and liver cirrhosis (O'Sullivan et al. 2002), as well as with the evolution of aneuploidy on the single-cell level in human hepato-cellular carcinoma (Plentz et al. 2005).

Telomere Shortening

Telomere Dysfunction

Fig. 11.2 Telomere shortening increases tumor initiation. Different mechanisms can increase the tumor risk in response to telomere shortening and telomere dysfunction: (i) Telomere dysfunction induces chromosomal instability by inducing fusion-bridge-breakage cycles resulting in aneuploidy and non-reciprocal tranlocations; (ii) cell with dysfunctional telomeres show an activation of stress signalling pathways (p38) leading to a an increased secretion of cytokines and growth factors from senescent cells; (iii) telomere shortening limits the proliferation of stem and progenitor cells in organs. This loss of proliferative competition leads to a selection of malignant stem and progenitor cells that have an increased or abnormal proliferation capacity

Fig. 11.2 Telomere shortening increases tumor initiation. Different mechanisms can increase the tumor risk in response to telomere shortening and telomere dysfunction: (i) Telomere dysfunction induces chromosomal instability by inducing fusion-bridge-breakage cycles resulting in aneuploidy and non-reciprocal tranlocations; (ii) cell with dysfunctional telomeres show an activation of stress signalling pathways (p38) leading to a an increased secretion of cytokines and growth factors from senescent cells; (iii) telomere shortening limits the proliferation of stem and progenitor cells in organs. This loss of proliferative competition leads to a selection of malignant stem and progenitor cells that have an increased or abnormal proliferation capacity

Experimental support for the telomere hypothesis of cancer initiation has come from studies in mTERC-'- mice. Increased tumor initiation in mTERC-'- mice was associated with increased rates of chromosomal instability in tumor cells (Artandi et al. 2000). These studies have also shown that heterozygous deletion of p53 can increase CIN and tumor initiation specifically in epithelial compartments (Artandi et al. 2000). The molecular basis of increased cancer formation in response to telomere dysfunction and checkpoint abrogation remains to be defined. Virtually all tumors in mTERC-'-, p53+/- mice showed a loss of heterozygosity of the remaining p53 allele, indicating that telomere dysfunction can increase LOH, which then promotes cancer formation. In addition, the tumors showed high rates of CIN, including nonreciprocal translocations - a hallmark of human cancer during ageing. It is an interesting area of investigation to map these chromosomal lesions aiming to identify recurrent lesions that are functionally involved in carcinogenesis (O'Hagan et al. 2002).

In addition to its role in initiation of CIN, telomere dysfunction could promote tumor formation by inducing environmental alterations. Primary human fibroblasts develop a secretory phenotype in response to telomere dysfunction and senescence (Parrinello et al. 2005). Senescent fibroblasts secrete elevated amounts of proinflammatory cytokines and matrix-modulating proteins. Co-culture experiments indicate that these secreted factors alter proliferation and differentiation of epithelial cells (Parrinello et al. 2005). Studies in mTERC-/- mice have provided evidence that the secretory phenotype occurs in response to telomere dysfunction in vivo. Telomere dysfunction in late-generation mTERC-/- mice induces environmental alterations that impair the function and engraftment of hematopoietic stem cells (Ju et al. 2007; see also Gutierrez and Ju, this volume). It is conceivable that such environmental alterations would influence the selective outgrowth of (pre-) malignant cell clones in ageing organs and tissues, thus promoting cancer formation (Fig. 11.2). Moreover it is possible that loss of proliferative competition itself promotes cancer formation in response to telomere shortening. It has been shown that the loss of replicative competition of hematopoietic stem and progenitor cells promotes selective outgrowth of malignant hematopoietic clones and leukemogenesis (Bilousova et al. 2005). It is conceivable that telomere shortening would induce the same process, since it impairs the proliferative capacity of stem and progenitor cell compartments (Choudhury et al. 2007).

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