Telomerase and Cancer

Both DC and ageing exhibit an increased incidence of cancer (Alter 2000, Dokal 2000). While telomerase activity is undetectable in most somatic cells, above 85% of tumors express telomerase (Counter et al. 1992, Kim et al. 1994). Reactivation of telomerase is therefore regarded as a crucial step in the development of cancer. It has been observed that expression of TERT is sufficient for immortalizing primary cells (Bodnar et al. 1998, Vaziri and Benchimol 1998). Additionally, mice deficient for telomerase exhibited resistance to tumorigenesis (Greenberg et al. 1999, Gonzalez-Suarez et al. 2000; see also Blasco, this volume). A recent study reported that a virus-encoded telomerase RNA promotes formation of T cell lymphoma in chicken, highlighting the significance of TERC in oncogenesis (Trapp et al. 2006). The hypothesis that elevated expression of TERT or TERC is positively related with cancer occurrence raises the question why there is increased cancer susceptibility in DC and ageing where telomerase is deficient or telomeres are massively shortened. The possible explanation is that progressive telomere shortening increases genome instability, which subsequently leads to malignancy (Marciniak et al. 2000, Greenberg 2005, Mason et al. 2005, Rudolph et al. 1999 and 2001). According to the model of pathogenesis of DC proposed by us (Fig. 5.5), excessive telomere shortening induced by telomerase deficiency leads to cell cycle arrest (senescence) or cell death (apoptosis) in rapidly dividing cells, including bone marrow cells. The increased requirement for replenishment results in recruitment of more quiescent stem cells into the cell cycle and subsequent proliferation, which in turn accelerates telomere shortening, senescence, and apoptosis. This will ultimately result in an early exhaustion of the stem cell compartment, causing the clinical manifestations of bone marrow failure. In some cases, few cells survive from the telomere-based crisis, possibly via mutated p53 genes which enable the cells to proliferate beyond the senescence checkpoint (Artandi and DePinho 2000). These cells have gained the property of genome instability as the eroded telomeres can no longer protect the chromosome ends from fusion and recombination, thus becoming potential malignant cells. This model coincides with the increased risk of cancer in the ageing population where accumulation of cell damage and oxidative stress over time increases the chance of genome instability (Weinstein and Ciszek 2002). In addition to the increase in chromosomal instability, telomere shortening may induce cancer progression by impairing the replicative competition of progenitor cells (Bilousova et al. 2005; see also Rudolph, this volume).

The reactivation of telomerase in the majority of tumor types underscores the importance of telomere maintenance in tumor pathogenesis. This is further supported by the fact that in those tumor cells that do not express telomerase, an alternative telomerase- independent (ALT) pathway is required to maintain telomere length (Bryan et al. 1997, Dunham et al. 2000). It is therefore plausible that telomerase contributes to cancer development by extending telomeres. However, in recent years, several studies have shown that TERT may play a role in proliferation and tumorigenesis that is independent of telomere maintenance. Transgenic expression of TERT in mice promoted the formation of carcinogen-induced skin

Fig. 5.5 Model of the pathogenesis of dykeratosis congenita and ageing. (A) X-linked DC and DKC1 gene mutation. (B) AD-DC and TERC gene mutation. (C) AD-DC and TERT gene mutation. (D) Ageing. Mutations in multiple components of the telomerase complex are identified in patients with dyskertatosis congenita, suggesting that excessive telomere shortening is the underlying cause of this disease. (A-C) The critically shortened telomeres lead to cell cycle arrest and/or cell death in rapid dividing cells including stem cells and early progenitor cells. The cell senescence/death results in the recruitment of more stem cells into cell cycle. Consequently, the increased proliferation of a decreased number of stem cells aggravates the rate of telomere shortening, which ends up with the depletion of the stem cells and the development of disease phenotype. Mutations in TERC or TERT directly reduce the enzymatic activity of telomerase and disrupt its function in telomere maintenance (B and C). Anticipation refers to early onset and more severity in successive generations in AD DC, which suggests that several generations may be required for haploinsufficiency for TERC or TERT to produce clinically detectable phenotype. Mutations in DKC1 may either destabilize the structure of TERC that causes deregulation the telomerase activity or/and reduce pseudouridylation and retard the rate of ribosome biogenesis (which were observed in mice carrying DKC1 mutation (A) that leads to cell cycle arrest/cell death of stem cells and their progeny. On the other hand, the few cells that survive the crisis accumulate genomic instability due to excessively short telomeres and become potentially malignant cells, leading to MDS (myelodysplastic syndrome), AML (acute myelogenous leukemia), or other types of cancer. In the ageing process (D), telomeres shorten in multiple organs, suggesting that normal somatic cells devoid of telomerase activity undergo telomere shortening during cell division, leading to cell senescence and organism ageing. Critically short telomeres in ageing populations, similar to those in dyskeratosis congenita, result in chromosomal instability and increased susceptibility to age-related disease and cancer. Nevertheless, telomere shortening is not the only cause for the pathogenesis of ageing. Other pathways such as accumulation of genetic mutations, unbalanced metabolic rate, and oxidative stress also contribute to the disease phenotype in ageing (See Color Plate)

papillomas and increased occurrence of mammary carcinoma (Gonzalez-Suarez et al. 2001, Artandi et al. 2002). The tumorigenic effect of TERT is not likely due to elongating telomeres since mice have extremely long telomeres. In cells that use the ALT mechanism to maintain telomere length, expression of TERT or TERC was shown to be necessary for tumor transformation, growth, or metastasis

(Stewart et al. 2002, Chang et al. 2003). The augmentation of proliferative potential by overexpression of TERT was thought to be mediated by the abrogation of the growth-inhibiting effect in transforming growth factor-ß (Geserick et al. 2006). A vTERC encoded by a herpesvirus that has 88% sequence homology with cTERC was found to enhance tumorigenesis (Trapp et al. 2006), suggesting a possible role of TERC as an oncogene. The mechanism behind the oncogenesis induced by vTERC in terms of whether telomere stabilization is involved is not known, but vTERC did exhibit higher potential for reconstitution of telomerase activity in the presence of TERT compared with cTERC (Fragnet et al. 2005). Telomerase was also found to have multiple effects on skin stem cells in mice. It was reported that in transgenic mice overexpressing TERT, skin wound healing and formation of epidermal tumors were promoted without obvious elongation of telomeres (Gonzalez-Suarez et al. 2001). A recent study also showed that overexpression of TERT in epidermal stem cells enhances mobilization, proliferation, and hair growth in the absence of effects on telomere length (Sarin et al. 2005; see also Artandi, this volume). Still further, the proliferation of hair follicle stem cells induced by TERT was found to be independent of the presence of TERC, suggesting a noncanonical role that goes beyond the extension of telomeres (Blasco 2002).

0 0

Post a comment