Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes

Abstract

Telomerase transgenics are an important tool to assess the role of telomerase in cancer, as well as to evaluate the potential use of telomerase for gene therapy of age-associated diseases. Here, we have targeted the expression of the catalytic component of mouse telomerase, mTERT, to basal keratinocytes using the bovine keratin 5 promoter. These telomerase-transgenic mice are viable and show histologically normal stratified epithelia with high levels of telomerase activity and normal telomere length. Interestingly, the epidermis of these mice is highly responsive to the mitogenic effects of phorbol esters, and it is more susceptible than that of wild-type littermates to the development skin tumors upon chemical carcinogenesis. The epidermis of telomerase-transgenic mice also shows an increased wound-healing rate compared with wild-type littermates. These results suggest that, contrary to the general assumption, telomerase actively promotes proliferation in cells that have sufficiently long telomeres and unravel potential risks of gene therapy for age-associated diseases based on telomerase upregulation.

Somatic stem cells and the origin of cancer

“…In contrast, telomerase activation promoted stem cell mobilization and proliferation. These findings may explain the increased susceptibility of mTERT mice to develop skin tumors and anticipate a critical role of telomerase and telomere length in the regulation of cancer stem cells 97,98,102 .…”

“…This finding is not totally unexpected, as alterations in telomere length and telomerase activity may facilitate cancer development by regulating genomic stability and cell lifespan 95 . In fact, a combination of shortened telomeres and increased telomerase activity is seen in most hematological and solid tumors 96 and mTERT transgenic mice with increased telomerase activity spontaneously develop cancer 97 . The best model to study telomere functions in stem cells has been the hematopoietic cell compartment 95,98 .…”

“…Still, the idea of cancer as a consequence of stem cell niche mutations is hypothetical, although recent data support the role of the vascular niche in initiating metastasis 152 . In addition, skin tumors can be caused by telomerase activation, which promotes epidermal stem cell mobilization out of their niche together with increased cell proliferation 97,103 . The study of signalling pathways that control mobilization and homing of stem cells in the niche will enhance our understanding of cancer development, invasiveness, and metastasis.…”

Aging by epigenetics—A consequence of chromatin damage?

“…Specifically, senescent cells and/or molecular markers of the senescent phenotype have been reported to increase in some aging tissues [40,41,[64][65][66][67][68][69], and are linked to some age-associated tissue pathologies, such as osteoarthritis, atherosclerosis and liver cirrhosis [70][71][72]. Moreover, manipulation of the cell signals that initiate senescence, such as telomere length and expression of the proliferation inhibitor p16INK4a [66][67][68]70,[73][74][75][76][77][78][79][80], can modulate some aspects of organismal aging [70][71][72]. In addition to a likely role in tissue aging, cellular senescence is also a well-established tumor suppression process, by virtue of its ability to arrest proliferation and neoplastic progression of cells harboring oncogenic lesions [81][82][83][84][85][86][87].…”

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

“…42 To some extent, telomerase activity may be associated with tumor development as some tumor cells show elevated telomerase activity and can still maintain long telomeres without pronounced telomerase activity. Moreover, initial tumor formation can occur independently from telomerase activation.…”