CORRESPONDENCE

RESPONSE: Re: Effects of N-(4-Hydroxy-phenyl)retinamide on hTERT Expression in the Bronchial Epithelium of Cigarette Smokers

Jean-Charles Soria, Chulso Moon, Li Mao

Affiliations of authors: J.-C. Soria, Division of Cancer Medicine, Institut Gustave Roussy, Villejuif, France; C. Moon, Department of Oncology and Head and Neck Cancer Research Institute, Johns Hopkins University School of Medicine, Baltimore, MD; L. Mao, Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston.

Correspondence to: Li Mao, M.D., Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Box 432, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: lmao{at}mdanderson.org).

Bowman et al. confirmed our earlier observation that the human telomerase reverse transcriptase calatylic subunit (hTERT) is expressed in microscopically normal bronchial epithelia by analyzing hTERT mRNA expression in pathological samples from 28 patients who underwent definitive surgical resection for stage I–III non-small-cell lung cancer. In our study, hTERT mRNA was detectable, by in situ hybridization, in 64% of the 266 bronchial biopsies obtained before treatment from active or former smokers enrolled in a chemoprevention trial (1,2). Bowman et al., by real-time polymerase chain reaction (RT–PCR), found that 10 (36%) of 28 bronchial epithelial scrapes expressed hTERT mRNA. Notably, the levels of hTERT expressed in bronchial epithelia were comparable to those expressed in the corresponding tumors. Because in situ hybridization measures gene expression of individual cells whereas RT-PCR measures gene expression in cell populations, the frequencies observed in the two studies cannot be directly compared. Nevertheless, the data indicate that hTERT expression is a frequent event in the early stage of tobacco-induced lung carcinogenesis.

How tobacco carcinogens induce expression of hTERT remains unclear. Bowman et al. suggest that cytotoxic components of tobacco smoke may cause epithelial injury, which in turn stimulates epithelial cell proliferation. However, we found no direct association between hTERT expression and the Ki-67 labeling index, a measure of cell proliferation (1). An alternative explanation for how hTERT is activated by tobacco carcinogens involves the apparent targeting of telomeric sequences by tobacco-related DNA adducts. Indeed, smoking-related DNA adducts are common at deoxyguanosine residues, which are found in high levels at telomeres (3). Tobacco-induced "telomeric stress" might therefore contribute to hTERT expression and telomerase activation. From this perspective, it is important to evaluate a potential role for hTERT in the genomic instability that has been observed in the bronchial epithelium. In such a context, expression of hTERT could therefore be a double-edged event. On the one hand, it provides cells with an unlimited replicating capacity, whereas on the other hand, it prevents development of genomic instability (4).

Another issue requiring further investigation is whether hTERT expression in the bronchial epithelia of smokers is a marker of increased risk of developing lung cancer. This issue will be best evaluated by a careful follow-up of such smokers. It is also necessary to determine whether hTERT is expressed in the bronchial epithelia of light smokers and nonsmokers, because our data and the data reported by Bowman et al. are mainly based on a population of heavy smokers with a mean cumulative tobacco exposure of 50 pack-years (1). Statistically speaking, only one in 10 heavy smokers will develop lung cancer in their lifetime (5), whereas the rate of hTERT expression in such a population is much higher (1). Therefore, this abnormality alone is not sufficient to determine a true lung cancer risk and should be integrated with other molecular abnormalities, such as those that cause inactivation of tumor suppressor genes, to better predict the risk of lung cancer development. In that regard, we have recently demonstrated that promoter hypermethylation can be detected in exfoliated cells from the bronchial trees of former smokers (6).

REFERENCES

1 Soria JC, Moon C, Wang L, Hittelman WN, Jang SJ, Sun SY, et al. Effects of N-(4-hydroxyphenyl)retinamide on hTERT expression in the bronchial epithelium of cigarette smokers. J Natl Cancer Inst 2001;93:1257–63.[Abstract/Free Full Text]

2 Kurie JM, Lee JS, Khuri FR, Mao L, Morice RC, Lee JJ, et al. N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium. Clin Cancer Res 2000;6:2973–9.[Abstract/Free Full Text]

3 Mustonen R, Schoket B, Hemminki K. Smoking-related DNA adducts: 32P-postlabeling analysis of 7-methylguanine in human bronchial and lymphocyte DNA. Carcinogenesis 1993;14:151–4.[Abstract]

4 Hackett JA, Greider CW. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene 2002;21:619–26.[Medline]

5 Mattson ME, Pollack ES, Cullen JW. What are the odds that smoking will kill you? Am J Public Health 1987;77:425–31.[Abstract]

6 Soria JC, Rodriguez M, Liu DD, Lee JJ, Hong WK, Mao L. Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers. Cancer Res 2002;62:351–5.[Abstract/Free Full Text]



             
Copyright © 2002 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement