October - December 2007: 
Volume 20, Issue 4

Click on the image to download the Issue in PDF format.


Telomeres, telomerase and immortality: A common link between lung cancer and pulmonary fibrosis
Full text

It is known that cells in most tissues and organs exhibit a limited lifespan, but why cells in different tissues have a different lifespan is not fully understood. This difference has been recognized to depend on mechanisms involving telomeres1. Telomeres, which are specialized nucleoprotein structures, are found at the ends of eukaryotic chromosomes and are composed of short tandem DNA repeats and a multitude of associated proteins. Telomerase is a specific multi-subunit ribonucleoprotein that catalyzes the addition of TTAGGG telomere DNA at the ends of linear chromosomes, compensating for the telomere erosion that normally occurs with each cell division, and contributing to the stability, function and replication of chromosomes. It consists of two essential components: a catalytic component, telomerase reverse transcriptase (h-TERT) and an RNA component (hTR)2.

Telomerase has been shown to be crucial for the extended life span, proliferation and differentiation of cells, and has been linked to immortality in cancer cell lines3. Compelling evidence supports the notion that expression or induction of telomerase activity is not restricted to immortalized cancerous or transformed cells3, but is also associated with tissue injury and with fibroproliferative disorders characterized by increased proliferation and survival of fibroblastic-like cells, including idiopathic pulmonary fibrosis (IPF). The pathogenetic hallmarks of IPF are increased alveolar cell apoptosis and fibroblastic foci, which are areas rich in highly proliferative mesenchymal cells and extracellular matrix, constituting the histopathologic pattern of usual interstitial pneumonia (UIP)4. Recent evidence supports the concept that the active fibrosis of IPF reflects abnormal wound repair in response to multiple foci of ongoing alveolar epithelial injury, whereas other types of pulmonary fibrosis, such as cryptogenic organizing pneumonia (COP), which is characterized by distinct fibromyxoid lesions called Masson bodies (MB), that are capable of even complete reversal, represent normal wound repair in response to a single injurious stimulus4. It has been shown in recent years that even the alveolar epithelium, which had been thought to be a passive bystander in the process of pulmonary fibrosis, may be subject to repeated epithelial injury which induces transition of regenerative alveolar epithelial cells (AEC) to a mesenchymal phenotype (epithelial-mesenchymal transition-EMT), thus contributing directly to fibrogenesis5. The unremitting recruitment and maintenance of the altered fibroblast phenotype, with generation and proliferation of immortal fibroblasts, coupled with the EMT phenomenon, is reminiscent of the transformation of cancer cells and metaplasia.

While there is increasing evidence to support the role of telomerase in tumorigenesis, its contribution to fibrogenesis remains unclear. Experimental findings have demonstrated that telomerase activity is selectively induced in fibroblasts isolated from bleomycin-injured rat lungs, presumably before their differentiation to myofibroblasts6,7. This evidence was extended by the observation that the loss of telomerase activity is closely associated with myofibroblast differentiation and possibly functions as a triggering factor for this procedure8,9. In addition, Fridlender et al. implicated low telomerase activity in robust apoptosis of AECs isolated from mouse lungs after treatment with bleomycin10. However, human and mouse telomerases are reported to differ in both their functional properties and their regulation, while the bleomycin-animal model is not fully representative of IPF11. Recently published genetic linkage studies12,13 in patients with familial IPF demonstrated pulmonary fibrosis as a human-specific manifestation of telomerase deficiency, as seen in the phenotype of congenital dyskeratosis, a rare syndrome characterized by mutations in the telomerase complex and pulmonary fibrosis resembling IPF. Specifically, a primary role for mutant telomerase components in the pathogenesis of IPF was described, suggesting that the presence of dysfunctional telomerase components results in short telomeres in AECs, ultimately leading to cell apoptosis and triggering the fibrogenic process through epithelial-mesenchymal interactions12,13.

Unpublished data derived from the author’s laboratory further support these observations: real time qRT-PCR was used, which showed down-regulation of telomerase expression in IPF lung compared to control samples. In addition, two tissue microarray blocks were constructed, comprising 100 representative tissue samples from patients with sporadic IPF and COP and control subjects. Immunostaining studies coupled with computerized image analysis revealed decreased telomerase expression in IPF and COP lung samples compared to controls. Immunolocalization studies identified two distinct subpopulations of AECs based on their telomerase expression levels: telomerase positive type II AECs, mainly overlying areas of active fibrosis exhibiting high levels of differentiation markers, and telomerase negative type II AECs, mainly localized in areas of established fibrosis and expressing increased levels of apoptosis14.

A simple model that emerges from these observations is that mutations in telomerase genes are responsible for either reduced telomerase expression and shortened telomeres, resulting in loss of AECs, or increased expression leading to hyperplasia and transition to a mesenchymal phenotype, a form of metaplasia. However, these data raise the important biological question of at what point during disease development and the stepwise progression of normal AECs towards transformation does telomerase become activated. It is tempting to speculate the existence of a specific checkpoint beyond which loss of telomerase activity due to injurious stimuli and/or inherited mutations may lead to loss of AECs and promote genomic instability. Activation of telomerase after the onset of genomic instability, coupled with a repeatedly injurious microenvironment, may affect the physiological differentiation of normal alveolar epithelial progenitors towards a transformed mesenchymal phenotype, resulting in abnormal reepithelization and contributing to the fibrogenic process. Addressing this issue may provide a way forward. Treatment targeted at enhancing telomerase activity or delaying telomere shortening early during disease development, before genomic instability occurs, may lead to new, more effective forms of treatment for this dismal disease. Finally, telomerase activity and telomere length may serve as surrogate markers for the identification of patients at greater risk for carrying mutant telomerase genes and developing pulmonary fibrosis.


1. Wong JM, Collins K. Telomere maintenance and disease. Lancet 2003, 362:983-988.
2. Counter CM, Avilion AA, LeFeuvre CE, et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 1992, 11:1921-1929.
3. Nakayama J, Tahara H, Tahara E, , et al. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet 1998, 18:65-68.
4. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001, 134:136- 151.
5. Strieter RM. Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 2005, 128:526S-532S.
6. Liu T, Nozaki Y, Phan SH. Regulation of telomerase activity in rat lung fibroblasts. Am J Respir Cell Mol Biol 2002, 26:534-540.
7. Nozaki Y, Liu T, Hatano K, Gharaee-Kermani M, Phan SH. Induction of telomerase activity in fibroblasts from bleomycin-injured lungs. Am J Respir Cell Mol Biol 2000, 23:460-465.
8. Liu T, Hu B, Chung MJ, Ullenbruch M, Jin H, Phan SH. Telomerase regulation of myofibroblast differentiation. Am J Respir Cell Mol Biol 2006, 34:625-633.
9. Schissel SL, Layne MD. Telomerase, myofibroblasts, and pulmonary fibrosis. Am J Respir Cell Mol Biol 2006, 34:520-522.
10. Fridlender ZG, Cohen PY, Golan O, Arish N, Wallach-Dayan S, Breuer R. Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis. Eur Respir J 2007, 30:205- 213.
11. Phan SH. Fibroblast phenotypes in pulmonary fibrosis. Am J Respir Cell Mol Biol 2003, 29:S87-S92.
12. Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007, 356:1317-1326.
13. Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U.S.A. 2007, 104:7552-7557.
14. Tzouvelekis A, Tsiambas E, Karameris A, et al. Induction of Telomerase Expression in Alveolar Type II Epithelial Cells in Patients with Idiopathic Pulmonary Fibrosis and Cryptogenic Organizing Pneumonia. A Tissue Microarray Study . Am J Respir Crit Care Med 175, A984. 2007. Ref Type: Abstract.