But Suppresses Tumor Progression in Telomerase Deficient Mice

Similar to the results in human cancer, studies in telomerase knockout mice have revealed a dual role of telomere shortening in cancer formation.

Telomerase knockout mice lack the RNA component of telomerase (mTERC-/-, Blasco et al. 1997; see also Blasco, this volume). First-generation (G1) mTERC-/- mice do not show an obvious organ phenotype due to long telomere reserves in laboratory mouse strains (Prowse and Greider 1995). When G1 mTERC-/- mice are crossed with each other, significant telomere shortening is seen in the second generation of knockout mice (G2). Using this mating scheme, successive telomere shortening occurs from one generation to the next, resulting in critically short telomeres and telomere dysfunction in late-generation animals (G3-G6, Blasco et al. 1997). The onset of telomere dysfunction depends on the initial telomere length in individual mouse strains. Mouse strains with relatively short telomeres reach a critically short length in earlier generations compared to mouse strains with longer telomeres (Herrera et al. 1999). Late generation mTERC-/- mice show a variety of premature ageing phenotypes predominantly affecting stem cell compartments and organ systems with high rates of cell turnover (Rudolph et al. 1999, Herrera et al. 1999, Choudhury et al. 2007; see also Chang, this volume; Gutierrez and Ju, this volume; Artandi, this volume; Blasco, this volume).

In line with the model that telomere shortening represents a tumor suppressor mechanism, late-generation mTERC-/- mice show an impaired development of macroscopic cancers in response to carcinogen treatment (Gonzalez-Suarez et al. 2000, Farazi et al. 2003) or when crossed with tumor-prone, genetic mouse models of cancer (Greenberg at al. 1999a, Rudolph et al. 2001). In contrast to its role in tumor suppression, telomere shortening in mTERC-/- mice is also associated with increased rates of cancer initiation. mTERC-/- mice on a mixed genetic background showed increased rates of spontaneous cancer formation during ageing (Rudolph et al. 1999). Moreover, APC-mutant mice exhibited an increased rate of intestinal tumor initiation (microadenoma and dysplastic crypts) when crossed with mTERC-/-mice (Rudolph et al. 2001). Similarly, the rate of liver tumor initiation in response to carcinogen-treatment was increased in late-generation mTERC-/- mice compared to mTERC+/+ mice (Farazi et al. 2003). Moreover, mTERC deficiency accelerated cancer formation in response to destabilization of telomeres induced by TRF2 overexpression (Blanco et al. 2007; see also Blasco, this volume). Together, these data indicate that telomere dysfunction suppresses tumor progression in tumor-prone mice but, in contrast, can increase tumor initiation during ageing and in response to genetic lesions or carcinogen exposure.

There is evidence that loss of checkpoint function can accelerate tumor formation in response to telomere dysfunction, specifically the loss of p53 checkpoint function (Chin et al. 1999). Moreover, heterozygous deletion of p53 cooperated with telomere dysfunction and increased the incidence of epithelial cancers in ageing mTERC-/-, p53+/- mice (Artandi et al. 2000). This finding is interesting since an increase in epithelial cancer is a hallmark of human ageing, which is characterized by telomere shortening, and often the tumors show defects in p53 checkpoint function (see above and Satyanarayana et al. 2004, Lowe et al. 2004).

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