Telomere Shortening and Telomerase Activation Characterize Human Tumorigenesis

Most somatic tissues in adult humans lack telomerase activity. The absence of telomerase expression and the end replication problem of DNA-polymerase lead to a continuous shortening of telomeres in replicating cells (see Allsopp, this volume). In addition, the accumulation of reactive oxygen species (ROS) can accelerate telomere shortening (see Passos et al., this volume). During ageing significant telomere shortening occurs in most human tissues and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover (for review see Djojosubroto et al. 2003).

The telomere hypothesis of cellular ageing indicates that telomere shortening represents a tumor suppressor mechanism. In response to critical shortening, telomeres lose capping function and dysfunctional telomeres induce cell cycle arrest, senescence, or apoptosis (Wright and Shay 1992, Chin et al. 1999, d'Adda di Fagagna et al. 2003, Herbig et al. 2004, Choudhury et al. 2007; see also Gutierrez and Ju, this volume). Telomere shortening and the activation of these checkpoints constrain cell proliferation and prevent immortal proliferation of cells (Wright and Shay 1992). Telomere shortening and the activation of these checkpoints. This mechanism

K. Lanhard Rudolph

Institute of Moleculare Medicine and Max-Planck-Research-Group on Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany e-mail: [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg protects organisms from cancer, since the proliferative capacity of transformed cancer cells that arise during a lifetime is limited by telomere shortening not allowing tumor mass growth or metastasis. In agreement with this hypothesis, over 80% of human cancers show an activation of telomerase (for review see Satyanarayana et al. 2004, Ju and Rudolph 2006) - the enzyme, which stabilizes telomeres thus facilitating immortal proliferation of cells (see Artandi, this volume). The activation of telomerase is a general phenomenon in different types of human cancer, thus making it a promising target for cancer therapy (Shay and Wright 2002, see also Keith and Bilsland, this volume). In human cancer the activation of telomerase often correlates with tumor progression. Premalignant tumors show no or very little telomerase activity, but an increase in activity is seen in malignant tumors and metastasis (for review see Satyanarayana et al. 2004). A subset of human cancers is telomerase negative. It has been postulated that these tumors exhibit alternative mechanisms of telomere lengthening (ALT). ALT has been demonstrated in experimental cell culture systems and appears to involve recombination of telomeric DNA (Muntoni and Reddel 2005). Together, we can conclude that an activation of telomere-maintenance mechanisms is a prerequisite for human cancer formation. This assumption was proven by cell culture experiments showing that the transformation of human cells into tumor-forming cancer cells requires the activation of telomerase (Hahn et al. 1999).

The above data indicate that suppression of telomerase in most somatic human tissues represents a tumor suppressor mechanism. According to this hypothesis, telomere shortening and loss of regenerative reserve during ageing and in response to chronic disease may represent a "side effect" of this tumor suppressor mechanism. This model is complicated by the fact that certain stem cell compartments in humans express tel-omerase activity such as the hematopoietic stem cells (HSC) as well as intestinal stem cells in the basal crypts (Yui et al. 1998, Tahara et al. 1999). An emerging hypothesis in molecular oncology indicates that stem cells represent the cell of origin of different types of cancers (Clarke et al. 2006). One could speculate that telomerase suppression is not a rate-limiting step in tumor formation since it is already expressed in stem cells (Armanios and Greider 2005). However, there is evidence that the level of telomerase expression in stem cells is not sufficient to maintain telomeres stable. It has been shown that CD34+ hematopoietic cells show significant telomere shortening during human ageing (Vaziri et al. 1994). Therefore, it seems likely that telomere shortening limits the proliferative capacity of human stem cells during ageing. In addition, these data suggest that transformed stem cells need to upregulate telomerase to achieve immortality. In agreement with this assumption, an upregulation of telomerase occurs in most malignancies of the hematopoietic system, which originate from telomerase-positive hemat-opoietic stem and progenitor cells (for review see Ju and Rudolph, 2006).

Another finding complicates the hypothesis that telomere shortening simply acts as a tumor suppressor mechanism: telomere shortening correlates with increased cancer risk. As summarized above most human tissues show significant telomere shortening during ageing. Telomere shortening during ageing is not associated with improved tumor suppression, but the cancer risk sharply increases during ageing (Hayat et al. 2007). Similarly, telomere shortening is associated with chronic diseases, which accelerate the rate of cell turnover, e.g., colitis ulcerosa, chronic hepatitis. In these diseases, critical telomere shortening correlates with the

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