A review of: Hahn WC, Stewart SA, Brooks MW, et al. 1999 Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5:1164–1170.

During each mitotic cycle, a portion of the terminal end (the telomere) of each chromosome is lost; eventually the chromosome reaches a critical degree of shortening at which point proliferation ceases and the cell dies. The RNA-protein enzyme telomerase supports de novo synthesis of telomeric DNA, resulting in maintenance of telomere length and proliferative potential.

Although most human somatic cells do not have demonstrable telomerase activity, it is present in cells of the fetus permitting continued proliferation and expansion of the organism. Indeed, with maturation of the fetus, telomerase levels fall progressively (1). As cells differentiate and age, telomerase levels decline. In culture, telomerase- negative cells can be rendered immortal by restoring telomerase activity (2). It could be postulated, therefore, that telomerase activity would be present in malignant cells in which there is unrestrained proliferation without differentiation.

Indeed, telomerase levels are elevated in the majority of malignant tumors and leukemias (2). For example, in neuroblastoma telomerase activity is high, whereas in the benign ganglioneuroma telomerase levels are low. In stage IV S neuroblastoma, which occurs in infants and may spontaneously disappear, telomerase levels are low. Furthermore, in other stages of neuroblastoma telomerase levels are directly related to prognosis (3).

This raises the question of whether the high telomerase levels of malignant cells are simply an associated feature or whether telomerase is responsible for the induction and/or continuation of the malignant state.

A recent study by Hahn et al. suggest that telomerase is central to the maintenance of the malignant state in human cells (4). The protein component of telomerase is a human telomerase reverse transcriptase, referred to as hTERT, which is lacking in somatic cells but expressed in immortalized cells. Hahn et al. created a catalytically inactive form of hTERT (referred to as DN-hTERT) which, when inserted into malignant cells (via a retroviral vector), had a “dominant negative” effect resulting in inhibition of telomerase activity. They inserted DN-hTERT into ovarian, breast, and colon cancer cell lines and into immortalized embryonic kidney cells. As a result, telomerase activity disappeared, telomere length shortened progressively, cell proliferation ceased, and the cells died by apoptosis. Evidently apoptosis occurs when telomeres reach a critically short length.

These observations indicated that, in vitro, cancer and embryonic cells were no longer immortal when telomerase was inhibited. The question remained, however, whether telomerase inhibition would prevent the tumorigenicity of these cells. They therefore injected DN-hTERT expressing cancer cells into immunodeficient nude mice. These cells produced no tumors, whereas the same cell line, expressing telomerase, induced tumors in all animals injected.

These observations indicate that telomerase is necessary not only for fetal cell proliferation and prevention of cellular aging, but also for the maintenance of the malignant state of cancer cells. It is clear that telomerase is a potential target for cancer therapy. Whether this is feasible and whether it will be successful remain to be seen.