González-Suárez E, Samper E, Flores J M, Blasco M A
Department of Immunology and Oncology, National Centre of Biotechnology, Madrid, Spain.
Nat Genet. 2000 Sep;26(1):114-7. doi: 10.1038/79089.
Inhibition of telomerase is proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumour growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumour therapy, as its inhibition is unlikely to have toxic effects. Mice deficient for Terc RNA (encoding telomerase) lack telomerase activity, and constitute a model for evaluating the role of telomerase and telomeres in tumourigenesis. Late-generation Terc-/- mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas). The appearance of these tumours is thought to be a consequence of chromosomal instability in these mice. These observations have challenged the expected effectiveness of anti-telomerase-based cancer therapies. Different cell types may nonetheless vary in their sensitivity to the chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms. Here we show that late-generation Terc-/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumour development in multi-stage skin carcinogenesis. Our results predict that an anti-telomerase-based tumour therapy may be effective in epithelial tumours.
有人提出，抑制端粒酶可通过引发端粒缩短和细胞死亡来限制癌细胞的生长。在某些细胞类型中，端粒酶维持端粒足以实现无限增殖。端粒酶已被证明可与癌基因协同作用，将培养的原代人细胞转化为肿瘤细胞，这表明端粒酶激活有助于恶性转化。此外，使用显性负性形式的端粒酶逆转录酶（TERT）抑制人肿瘤细胞系中的端粒酶会导致端粒缩短和细胞死亡。这些发现促使人们提出，抑制端粒酶可能导致肿瘤生长停止。大多数正常细胞中不存在端粒酶，这支持了抗端粒酶药物用于肿瘤治疗的潜在疗效，因为抑制端粒酶不太可能产生毒性作用。缺乏Terc RNA（编码端粒酶）的小鼠缺乏端粒酶活性，构成了评估端粒酶和端粒在肿瘤发生中作用的模型。晚期Terc-/-小鼠在增殖组织中表现出缺陷，在高增殖细胞类型（淋巴瘤、畸胎癌）中自发肿瘤的发生率适度增加。这些肿瘤的出现被认为是这些小鼠染色体不稳定的结果。这些观察结果对基于抗端粒酶的癌症治疗的预期效果提出了挑战。然而，不同细胞类型对端粒丢失引起的染色体不稳定或端粒拯救机制激活的敏感性可能不同。在这里，我们表明晚期Terc-/-小鼠端粒短且缺乏端粒酶，在多阶段皮肤癌发生过程中对肿瘤发展具有抗性。我们的结果预测，基于抗端粒酶的肿瘤治疗可能在上皮肿瘤中有效。
