Telomerase activity in normal and malignant mammalian tissues: feasibility of telomerase as a target for cancer chemotherapy

摘要

Telomerase, a ribonucleoprotein enzyme, has been found in immortalized but not in most somatic adult human tissues, and thus emerged as a novel target for cancer chemotherapy. However, its usefulness could still be limited by normal tissue toxicity. This study compares enzyme activity in tissues and tumours in conventional in vivo models and human biopsy material, specifically normal human liver, with a view to determining the therapeutic potential of anti-telomerase therapy. The telomeric repeat amplification protocol (TRAP assay) was used to measure enzyme activity and levels were semiquantified by assaying equal concentrations of cellular protein. Telomerase activity was high in the murine embryonic stem cell line CGR8.8, WRL 68 human embryo liver cells, testis, ovary and liver of adult mouse and rat. Low activity was detected in normal human liver, marmoset and pig liver. Very low enzyme activity was seen in mouse, rat and marmoset bone marrow, brain or skin; no activity could be detected in mammalian lung and heart. On the contrary, all 30 human and murine malignant tissues studied showed high to moderate enzyme levels. However, activity found in murine liver was often higher than in tumour, e.g. in the transplantable adenocarcinoma of the colon MAC16. Our findings indicate that telomerase is present not only in murine but also in other normal mammalian tissues such as liver, and that this activity might result from the presence of somatic stem cells. In view of this, the role of telomerase as a potential selective target for therapy needs further investigation. Furthermore, the understanding of regulatory pathways of this enzyme and the selection of screening models will be critical.