Mechanisms of telomere maintenance and attrition: linking cancer and ageing


In 1961 HayXick and Moorhead had already demonstrated that normal diploid Wbroblasts obtained from human fetal explants can be grown in culture for several months (HayXick and Moorhead, 1961). However, it soon became clear that it was impossible to subcultivate these cells for more than approximately 50 times and as they later lost the ability to divide, a phenomenon named replicative senescence, whose molecular mechanism was elucidated only decades later. However, the basic observation required for understanding the link between senescence and cancer was already made in the winter of 1951, when a 31-year-old patient, Henrietta Lacks, underwent a biopsy for a suspicious cervical mass (review Finkel et al. 2007). Routinely, the biopsy was sent to one particular pathology lab. Deviating from routine, a portion of the biopsy was instead diverted to two scientists, George and Martha Gey, who had spent almost 20 years unsuccessfully attempting to grow human cells indeWnitely in culture. Unfortunately, the biopsy was conWrmed to be cervical cancer and despite surgery and radiotherapy, Henrietta Lacks died 8 months later. On the day of her death Martha and George Gey announced that for the Wrst time, it was possible to continuously grow human cells in culture. In memory of the unfortunate Henrietta Lacks, the new cell line was named “HeLa”. A critical diVerence between the initially mentioned ‘normal’ Wbroblasts and HeLa cells is their quantity of telomerase. Most normal cells express only limited amounts of telomerase that are not suYcient to protect from telomere loss (Finkel et al. 2007). When telomere length falls below critical values, replicative senescence is induced. In contrast to Wbroblasts, HeLa cells, similar to more than 95% of the numerously later established human cancer cell lines, aberrantly activate telomerase leading to immortality (Kim et al. 1994). The Wnal proof that overexpressed telomerase is responsible for immortal growth came from experiments where telomerase was reintroduced into several primary human cell lines and shown to be suYcient to overcome replicative senescence (Bodnar et al. 1998). Meanwhile, it has become clear that the well-known tumor suppressors retinoblastoma (RB), P53 and P21 are key players in the induction of senescence. In addition to telomere shortening, overexpression of oncogenes may cause senescence (Trost et al. 2005; Spangenberg et al. 2006). Oncogene-induced senescence may be interpreted as a fail-safe mechanism that must be bypassed before tumor progression can take place (Hengstler et al. 2006). However, environmental factors such as cigarette smoking and further DNA damaging substances can also accelerate telomere attrition and senescence (Acosta and Gil 2009; Finkel et al. 2007), thereby linking Toxicology to telomere and ageing research. On the other hand, genetic instability and DNA breakage may lead to ampliWcation and increased expression of telomerase, although the involved mechanisms are not yet fully understood (Yatabe et al. 2004; Verdun and Karlseder 2007). Genetic instability (Florl and Schulz 2008; Hengstler and Bolt 2007, 2008; Stoiber et al. 2008; Beyersmann and Hartwig 2008) and DNA damage induction (Bolt 2008; Periyakaruppan et al. 2007; Borza et al. 2008; Bolt and Hengstler 2008; Zhang et al. 2008; Wong et al. 2008; Glahn et al. 2008; Krishnamurthi et al. 2008; Ullmann et al. 2008; Wozniak et al. 2007; Schmid et al. 2007; Nishimura et al. 2008; Schug et al. 2008) are J. G. Hengstler (&) · R. Marchan · H. M. Bolt Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany e-mail:

DOI: 10.1007/s00204-009-0428-9

Cite this paper

@article{Hengstler2009MechanismsOT, title={Mechanisms of telomere maintenance and attrition: linking cancer and ageing}, author={Jan G. Hengstler and Rosemarie Marchan and Hermann Maximilian Bolt}, journal={Archives of Toxicology}, year={2009}, volume={83}, pages={405-406} }