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Carcinogenesis, Vol. 20, No. 8, 1649-1652, August 1999
© 1999 Oxford University Press

Short Communications

Is small cell lung cancer the perfect target for anti-telomerase treatment?

Joseph Sarvesvaran, James J. Going1, Robert Milroy2, Stanley B. Kaye and W.Nicol Keith3

CRC Department of Medical Oncology, University of Glasgow, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD,
1 Glasgow University Department of Pathology, Royal Infirmary, Glasgow and
2 Department of Respiratory Medicine, Stobhill Hospital, Glasgow, UK


   Abstract
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 Abstract
Introduction
 References
 
Small cell lung cancer (SCLC) is common in men and women, has a very poor prognosis, and is therefore a major cause of premature mortality. As such, any prospects for improved therapy are of great significance. The promise of telomerase as a therapeutic target is now close to realization with extremely encouraging preclinical studies aimed at the RNA component (hTR) of telomerase. The rational integration of telomerase therapeutics into clinical trials will therefore require tumours to be well characterized for hTR expression. Despite the large number of cancer types now characterized for telomerase or telomerase component gene expression, only a handful of SCLC samples have been analysed. Given the major clinical problem with treating SCLC, we specifically set out to address the issue of hTR expression in neuroendocrine tumours. Our study covers 91 pulmonary neuroendocrine tumours (62 SCLC and 29 carcinoid tumours). We present data to show that upregulation of the RNA component of telomerase occurs in 98% of human SCLCs. Interestingly, the less aggressive carcinoid tumours of the lung had a significantly lower frequency of hTR expression (P < 0.01). Importantly, we compare hTR expression in this series to the well characterized biological targets p53 and BCL2, and show hTR to be expressed more frequently. Therapies directed at the RNA component of human telomerase are in active development and these data show SCLC to be a prime target for such therapies.

Abbreviations: hTR, human telomerase RNA component gene; SCLC, small cell lung cancer.


   Introduction
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 Abstract
 Introduction
References
 
Small cell lung cancer (SCLC) grows rapidly, metastasises early and, despite initial response to chemotherapy, the patient usually dies within 1–2 years. Thus, new treatments are required urgently (1–4). Recent insights into the molecular basis for oncogenesis have revealed new targets for cancer therapy (2), and one such target is telomerase (2,5,6). Telomerase plays a pivotal role in cancer development, is required for unlimited proliferation by cancer cells, and telomerase activation may be essential for cancer progression. Thus, telomerase activity and telomerase component gene expression are ideal candidates for therapeutic targeting (5–14). Antisense inhibition of the human telomerase RNA component (hTR), reduces telomerase activity in cell lines in culture and xenografts and causes cell death; it is likely that first-generation anti-telomerase therapies will target hTR (8,10–14). Preclinical development of hTR-based therapies will require clear understanding of patterns and frequencies of hTR gene expression in target tumour groups (7,15). We and others have examined non-small cell lung cancer for telomerase and hTR expression; however, despite its clinical importance, no large studies have yet addressed the frequency of hTR gene expression in SCLC (5,6,15,16). The majority of patients with SCLC have a good response to first line chemotherapy but relapse due to the rapid proliferation of residual disease. This may create a particularly advantageous context for telomerase-based therapies, as with more cell divisions required for the neoplastic clone to achieve life-threatening bulk again, there is greater scope for telomere shortening (in the absence of telomerase to maintain their length) to initiate cellular senescence and death (1,5).

We have examined 91 resected pulmonary neuroendocrine tumours of diverse clinical behaviour: 62 SCLC and 29 carcinoid tumours (Table IGo). hTR gene expression was analysed by RNA in situ hybridization to tissue sections from formalin-fixed, paraffin-embedded tissue blocks from pathology archives at Glasgow Royal Infirmary and Hairmyres Hospital, East Kilbride (Figure 1Go). Hybridizations were performed and evaluated as described (15). Immunohistochemical evaluation of p53 and BCL2 expression on serial sections used monoclonal antibodies DO7 (p53) and 124 (BCL2) with LSAB2 kit detection of antibody binding (all reagents from Dako, High Wycombe, UK).


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  		Table I. Frequency of hTR expression in neuroendocrine tumours
 


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  		Fig. 1. In situ detection of telomerase RNA gene expression in a carcinoid tumour of the lung (A) and two small-cell lung tumours (B and C). Hybridizations were photographed using a x40 objective lens. Inset are low power views (x10 objective lens) of the tissue sections for orientation purposes, with the box marking the area shown in detail in the higher power view. Hybridization signals are limited to the malignant cells. Levels of expression were comparable over the tumour, but absent over areas of central tumour necrosis. Section (A) has relatively low levels of hTR expression, (B) has intermediate levels of hTR expression and (C) has relatively high levels of hTR expression.

 
A total of 98% of SCLC had detectable levels of hTR gene expression (Table IGo; Figure 2Go). Interestingly, a high percentage of carcinoid tumours also express detectable levels of hTR, although at a significantly lower frequency than SCLC ({chi}2 = 25.52, df = 1, P < 0.01). Carcinoid tumours are not associated with smoking and are also less aggressive in their biological behaviour than SCLC (3,4). Tumours were also evaluated for p53 and BCL2 protein expression as these proteins are currently under clinical evaluation as biological targets for therapy (2). hTR expression in both SCLC and carcinoid tumours is more frequent than p53 or BCL2 protein expression (Figure 2Go). This suggests that the telomerase RNA component may currently represent the best available candidate for targeted therapy in SCLC. We have recently cloned the hTR gene promoter with a view to using this in gene therapies to target suicide genes to hTR-expressing cancer cells (7). Clearly, SCLC would be ideally suited to test such an approach as a primary therapy, a complement to induction chemotherapy or a maintenance therapy.



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  		Fig. 2. Frequency of telomerase RNA gene expression, BCL2 and p53 immunoreactivity, in 91 neuroendocrine tumours of the lung, consisting of 62 SCLCs and 29 carcinoid tumours.

 


   Acknowledgments
 
We thank Mr Jim Richmond (Glasgow Royal Infirmary) for immunocytochemistry, and Dr Arthur MacLay (Hairmyres Hospital) for case identification and access to tissue blocks. This work was supported by the Cancer Research Campaign, Glasgow University, the West of Scotland Lung Cancer Research Group and The Robertson Trust.


   Notes
 
3 To whom correspondence should be addressed Email: n.keith{at}beatson.gla.ac.uk Back


   References
Top
 Abstract
 Introduction
 References
 

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  3. Wang,D.G., Johnston,C.F., Sloan,J.M. and Buchanan,K.D. (1998) Expression of Bcl-2 in lung neuroendocrine tumours: comparison with p53. J. Pathol., 184, 247–251.[Web of Science][Medline]
  4. Brambilla,E., Negoescu,A., Gazzeri,S., Lantuejoul,S., Moro,D., Brambilla,C. and Coll,J.L. (1996) Apoptosis-related factors p53, Bcl2, and Bax in neuroendocrine lung tumors. Am. J. Pathol., 149, 1941–1952.[Abstract]
  5. Sharma,S., Raymond,E., Soda,H., Sun,D., Hilsenbeck,S.G., Sharma,A., Izbicka,E., Windle,B. and Von Hoff,D.D. (1997) Preclinical and clinical strategies for development of telomerase and telomere inhibitors. Ann. Oncol., 8, 1063–1074.[Abstract/Free Full Text]
  6. Urquidi,V., Tarin,D. and Goodison,S. (1998) Telomerase in cancer: clinical applications. Ann. Med., 30, 419–430.[Web of Science][Medline]
  7. Zhao,J.Q., Hoare,S.F., McFarlane,R., Muir,S., Parkinson,E.K., Black,D.M. and Keith,W.N. (1998) Cloning and characterization of human and mouse telomerase RNA gene promoter sequences. Oncogene, 16, 1345–1350.[Web of Science][Medline]
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Received February 12, 1999; revised May 4, 1999; accepted May 5, 1999.


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