High levels of telomere dysfunction bestow a selective disadvantage during the progression of human oral squamous cell carcinoma

Gordon, K.E., Ireland, H., Roberts, M., Steeghs, K., McCaul, J.A., MacDonald, D.G. and Parkinson, E.K. (2003) High levels of telomere dysfunction bestow a selective disadvantage during the progression of human oral squamous cell carcinoma. Cancer Research, 63(2), 458 -467.

Abstract

Human epithelial cells experience multiple barriers to cellular immortality in culture (mortality mechanisms 0, 1, and 2). Mortality mechanism 2 (M2) is termed crisis and involves telomere dysfunction due to lack of telomerase. However, proliferating normal keratinocytes in vivo can express telomerase, so it is unclear whether human squamous cell carcinomas (SCCs), which usually have high telomerase levels, develop from preexisting telomerase-positive precursors or by the activation of telomerase in telomerase-deficient somatic cells. We show that 6 of 29 oral SCCs show characteristics of M2 crisis in vivo, as indicated by a high anaphase bridge index (ABI), which is a good correlate of telomere dysfunction, and that 25 of 29 tumors possess some anaphase bridges. ABIs in excess of 0.2 in the primary tumor showed a decrease in the corresponding lymph node metastases. This suggests that high levels of telomere dysfunction (> 0.2) and, by inference, M2 crisis bestow a selective disadvantage on SCCs during progression stages of the disease. Supporting this, SCCs with high levels of telomere dysfunction grow poorly in culture, and the ectopic expression of telomerase corrects this, together with other features of M2 crisis. Our data suggest that a substantial proportion of oral SCCs in vivo ultimately arise from telomerase-deficient keratinocytes rather than putative telomerase-proficient cells in the undifferentiated parts of the epithelium. Furthermore, the presence of significant levels of telomere dysfunction in a high proportion of SCCs at diagnosis but not in the normal epithelium implies that the therapeutic inhibition of telomerase should selectively compromise the growth of such tumors

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McCaul, Dr James and Ireland, Mrs Hazel and Gordon, Mrs Karen
• Authors: Gordon, K.E., Ireland, H., Roberts, M., Steeghs, K., McCaul, J.A., MacDonald, D.G., and Parkinson, E.K.
• Subjects: R Medicine > RK Dentistry
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• ISSN: 0008-5472