Hiyama K, Hiyama E, Ishioka S, Yamakido M, Inai K, Gazdar A F, Piatyszek M A, Shay J W
Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center at Dallas 75235-9039, USA.
J Natl Cancer Inst. 1995 Jun 21;87(12):895-902. doi: 10.1093/jnci/87.12.895.
Telomerase is an enzyme that adds hexameric TTAGGG nucleotide repeats onto the ends of vertebrate chromosomal DNAs (i.e., telomeres) to compensate for losses that occur with each round of DNA replication. Somatic cells do not have telomerase activity and stop dividing when the telomeric ends of at least some chromosomes have been shortened to a critical length. It has been suggested that immortalized cells (including some, but probably not all, cancer cells) continue to proliferate indefinitely because they express telomerase.
To investigate whether expression of telomerase is a prerequisite for the development of naturally occurring human cancers, we assayed the levels of telomerase activity in specimens of human lung tumor and adjacent normal tissue.
Using a polymerase chain reaction-based assay, we examined telomerase activity in 136 primary lung cancer tissues and 68 adjacent noncancerous tissues obtained by surgical resection. We also studied telomerase activity in four primary and 23 metastatic lesions obtained through biopsy, (two patients) or autopsy (10 patients). Relative telomerase activity levels were estimated by serial dilutions of extracts prepared from the specimens. Telomerase activity was also assayed in extracts of cells present in pleural fluids from three patients with adenocarcinoma of the lung.
Among surgically resected samples, telomerase activity was detected in 109 (80.1%) of 136 primary lung cancer tissues and in three (4.4%) of 68 normal adjacent tissues. All 11 surgically resected specimens of primary small-cell lung cancer (from 11 patients) revealed high levels of telomerase activity, whereas the activity ranged from undetectable to high levels in the 125 surgically resected specimens of primary non-small-cell lung cancer tissue (from 125 patients). Generally, high levels of telomerase activity were observed in metastatic lesions and tumors with altered telomere length. A few primary and, surprisingly, some metastatic tumors did not appear to have detectable telomerase activity. Telomerase activity was, however, detected in cells present in all tested pleural fluids obtained (from three patients with adenocarcinoma of the lung).
The subset of non-small-cell lung cancers that exhibits only low or undetectable levels of telomerase activity may contain primarily mortal cancer cells. Cancers that exhibit high levels of telomerase activity, such as all of the small-cell lung cancers examined in this study, are likely to consist mainly of immortal cells.
Telomerase activity may be useful both as a diagnostic marker to detect the existence of immortal lung cancer cells in clinical materials and as a target for therapeutic intervention.
端粒酶是一种将六聚体 TTAGGG 核苷酸重复序列添加到脊椎动物染色体 DNA 末端（即端粒）的酶，以补偿每一轮 DNA 复制时发生的损失。体细胞不具有端粒酶活性，当至少一些染色体的端粒末端缩短到临界长度时就会停止分裂。有人提出，永生化细胞（包括一些但可能不是所有癌细胞）能够无限增殖是因为它们表达端粒酶。
为了研究端粒酶的表达是否是人类自然发生癌症发展的先决条件，我们检测了人肺肿瘤标本和相邻正常组织中端粒酶活性水平。
使用基于聚合酶链反应的检测方法，我们检测了 136 例原发性肺癌组织和 68 例手术切除获得的相邻非癌组织中的端粒酶活性。我们还研究了通过活检（2 例患者）或尸检（10 例患者）获得的 4 例原发性和 23 例转移性病变中的端粒酶活性。通过对标本提取物进行系列稀释来估计相对端粒酶活性水平。还检测了 3 例肺腺癌患者胸腔积液中细胞提取物的端粒酶活性。
在手术切除的样本中，136 例原发性肺癌组织中有 109 例（80.1%）检测到端粒酶活性，68 例正常相邻组织中有 3 例（4.4%）检测到端粒酶活性。所有 11 例手术切除的原发性小细胞肺癌标本（来自 11 例患者）均显示出高水平的端粒酶活性，而在 125 例手术切除的原发性非小细胞肺癌组织标本（来自 125 例患者）中，端粒酶活性水平从无法检测到高水平不等。一般来说，在转移性病变和端粒长度改变的肿瘤中观察到高水平的端粒酶活性。一些原发性肿瘤，令人惊讶的是，一些转移性肿瘤似乎没有可检测到的端粒酶活性。然而，在所有检测的胸腔积液（来自 3 例肺腺癌患者）中的细胞中都检测到了端粒酶活性。
仅表现出低水平或无法检测到端粒酶活性的非小细胞肺癌子集可能主要包含有寿命的癌细胞。表现出高水平端粒酶活性的癌症，如本研究中检测的所有小细胞肺癌，可能主要由永生化细胞组成。
端粒酶活性既可以作为一种诊断标志物来检测临床材料中永生化肺癌细胞的存在，也可以作为治疗干预的靶点。
