Telomerase and Early Detection of Cancer: a National Cancer Institute Workshop

Cellular immortality is a hallmark of cancer. The recent identification of telomerase, an enzyme associated with cellular immortality, at multiple points along the continuum of multistep carcinogenesis has created considerable interest in its potential for the early detection of carcinogenesis ( 1 , 2 ) . Telomerase is the enzyme that rebuilds telomeres, the TTAGGG-repeated ends of chromosomes. Germline cells express telomerase and are immortal. Although most fetal somatic cells express telomerase, the enzyme is considerably less active or inactive when the cells mature ( 3 ) . Thus, most somatic cells do not express telomerase and are mortal. Because of an end replication problem, i.e., incomplete synthesis of the lagging strand during DNA replication, the telomeres of mortal cells shorten with age and eventually reach a critical point at which chromosomal integrity is lost and proliferation ceases ( 1 ) . A rare somatic cell occasionally escapes programmed senescence(definition) by activating telomerase. The extended survival of such a cell could be conjectured to provide opportunities for the accumulation of additional genomic insults that might contribute to a progressive neoplastic evolution within that cell. If so, telomerase might serve as a key molecular marker of that process. The goal of early detection is to identify potentially carcinogenic or frankly carcinogenic lesions as early in multistep pathogenesis as possible ( 4 , 5 ) . Because the early detection of cancer is a dynamic process driven by continually advancing insights into the biology of carcinogenesis and both driven and limited by the availability of technologies, the meaning of “ early” is necessarily in constant flux. The nature of an ideal early detection biomarker, however, is unchanging; it should be expressed at a stage that allows interventions of greater efficacy or less toxicity than would be possible if it were detected later. Because telomerase might have potential as a biomarker for the early detection of cancer, the National Cancer Institute (NCI) convened the “ International Workshop on Telomerase in the Early Detection of Cancer” on June 6–7, 1996, in Bethesda, MD. The purpose of the workshop was to determine what is known about telomerase and what direction future research should take. In a keynote address, R. D. Klausner (Director, NCI) indicated NCI'ss continuing interest in research on telomere(definition) biology. B. S. Kramer (Deputy Director, Division of Cancer Prevention and Control, NCI) asked the panelists, experts in telomere and telomerase research, to consider the following questions related to the validity of telomerase as a biomarker for the early detection of cancer: What is the differential expression of telomerase among normal tissues and organs? Is telomerase present early in the multistep pathogenesis of cancer, and is it a sensitive and specific marker for preinvasive neoplasia? During their deliberations, the panelists raised a related question: Does telomerase predict the prognosis of cancer patients? The panelists also considered other central questions: Is some manifestation of telomerase, such as its RNA component or telomere length, more closely associated with the early detection of cancer than the enzyme itself, and can a reliable test for telomerase that is noninvasive or minimally invasive and easily administered by clinicians be developed? These questions and the panelists's responses are discussed below. Some normal renewal tissues express low levels of telomerase. These low levels of the enzyme compensate only partially for the end replication problem responsible for the progressive shortening of telomeres with age ( 1 ) . It is interesting that, in those renewal tissues that have detectable telomerase, telomeres continue to shorten throughout life, but perhaps at a slower rate. The question of differential expression is particularly important in determining whether the enzyme has sufficient specificity to be useful in the early detection of cancer within various target tissues. If a sample of nondiseased tissue contains a mixture of cell types, some of which normally express the enzyme, an individual might be incorrectly identified as diseased. Therefore, it is important to determine the levels of telomerase that are normal for each tissue or organ, accounting for the telomerase contributed by background expression, including normally present tissue components. The panelists presented data indicating that telomerase expression is considerably lower in normal renewal tissues than in cancerous tissues. Several workshop panelists reported that telomerase in the blood can be derived from mature cells as well as from stem cells. K. Hiyama (Hiroshima University School of Medicine, Japan) and S. Bacchetti (McMaster University Medical Center, Hamilton, ON, Canada) reported that normal peripheral mononuclear cells express telomerase, but at extremely low levels (i.e., about 1%-2% of the amount found in immortalized cancer cell lines) ( 6 , 7 ) . J. Ohyashiki (Tokyo Medical College, Japan) similarly reported that normal mononuclear cells express low levels of telomerase and that enzyme expression decreases with age (personal communication). C. Greider (Cold Spring Harbor Laboratory, NY) reported that resting T cells express low levels of telomerase that increase as cells progress in the cell cycle ( 8 ) . Her laboratory is currently conducting experiments to pinpoint the exact time of activation in G 1 . Several panelists presented data on levels of telomerase in the gastrointestinal tract. E. Hiyama (Hiroshima University School of Medicine) detected telomerase in normal intestinal mucosa, but at levels 10–100 times lower than in cancerous mucosa ( 9 ) ; he concluded that the enzyme might originate from intestinal basal stem cells. H. Tahara (Hiroshima University School of Medicine) also reported finding low levels of telomerase in normal gastrointestinal mucosa (personal communication). J. Shay (T