Increase in telomerase activity during progression of melanocytic cells from melanocytic naevi to malignant melanomas

Abstract

During successive cell divisions of mortal cells the length of the telomeres (TTAGGG repeats in vertebrates) at the end of chromosomes decreases. It has been suggested that this process is responsible for cellular senescence. Expression of the ribonucleoprotein telomerase appears to prevent shortening of telomeres in germ-line cells and cancer cells. The purpose of this study was to investigate telomerase activity in melanocytic lesions and its possible role in the multi-step tumor progression model of malignant melanoma. To quantify the level of telomerase activity both in cultured cells and in fresh tissue samples the TRAP (telomeric repeat amplification protocol) ELISA was used. Eight cell lines of malignant melanoma, 3 primary cultures of fibroblasts, 36 melanocytic naevi, 5 atypical melanocytic naevi, 3 Spitz's naevi, 31 primary malignant melanomas and 13 metastases of malignant melanomas were investigated. Also 34 samples of skin (22 samples of perilesional skin and 12 samples of normal skin) were analysed. In our experiments all melanoma cell lines were strongly positive, whereas in fibroblasts telomerase activity could not be detected. Of the primary melanomas and metastatic melanomas, 90.3% and 92.3%, respectively, were strongly positive, and of the atypical melanocytic naevi, 80% were positive. Of the 36 common melanocytic naevi only 10 (27.7%) expressed weak telomerase activity and of the 34 samples of human skin, 4 (11.7%) expressed very weak telomerase activity. Our results indicate that telomerase activity increases from benign melanocytic naevi to atypical naevi and further to malignant melanoma and metastatic melanoma cells, and therefore may play a role in tumour initiation and progression.

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

“…We also suggested that primary melanoma cells have emerged from senescence and immortalised (Bennett, 2003). Previous evidence for this includes the obvious property that melanoma cells proliferate, and the detection of telomerase activity in most melanomas and not in naevi (Glaessl et al, 1999;Rudolph et al, 2000). Explanted melanoma cells are not reported to senesce (Herlyn et al, 1985), growing so readily that thousands of melanoma cell lines exist.…”

“…We proposed a genetic model, in which benign and dysplastic naevi represent p16 and p53-dependent senescence, while melanomas arise by immortalisation of melanocytes (Bennett, 2003;Sviderskaya et al, 2003;Bennett, 2006). Published biological and molecular data (Talve et al, 1997;Keller-Melchior et al, 1998;Glaessl et al, 1999;Rudolph et al, 2000;Hussein and Wood, 2002;Bennett, 2003;Sviderskaya et al, 2003) were consistent with this model, but not conclusive, although a convincing report of cell senescence in melanocytic naevi has appeared recently (Michaloglou et al, 2005). We have now identified the genetic requirements for immortalisation of human melanocytes, and systematically studied molecular markers and mediators of cell senescence in clinical pigmented lesions of increasing malignancy.…”

Nevus Size and Number Are Associated with Telomere Length and Represent Potential Markers of a Decreased Senescence In vivo

“…Senescence is important in protecting cells against malignant transformation with age and all benign tumors are likely to be controlled by senescence signals (12). The role of the telomere pathway in melanocyte senescence is also apparent from work showing that telomerase activity increases steadily from benign nevi to dysplastic nevi to melanoma (36,37).…”

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

“…Telomerase activity has been reported in cutaneous melanomas, using the TRAP assay, with increasing values from normal skin to benign nevi and to dysplastic nevi and finally to melanoma [29]. An association between increased telomerase activity and worse prognostic features, namely, ulceration, vascular invasion, mitotic rate and Breslow thickness has been described in melanoma [18,32,81,91,100]. Furthermore, higher telomerase activity has also been associated with higher proliferation rate and early metastasis [100,104].…”