Affiliations of authors: Departments of Clinical Cancer Prevention (ALS, XX, SML) and Thoracic/Head and Neck Medical Oncology (ALS, SML), The University of Texas M. D. Anderson Cancer Center, Houston
Correspondence to: Anita L. Sabichi, MD, Department of Clinical Cancer PreventionUnit 1360, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., P.O. Box 301439, Houston, TX 77230-1439 (e-mail: asabichi{at}mdanderson.org).
Retinoids (vitamin A and its natural and synthetic analogues) have a strong preclinical record of anticarcinogenic activity in a broad range of tissue types (1). The promise of this record, however, has not been realized in clinical trials of retinoids in preventing lung cancers. The inability of retinoids to prevent second primary lung cancers in the phase III European Study on Chemoprevention with Vitamin A and N-Acetylcysteine (EUROSCAN) (2) and the Lung Intergroup Trial (LIT) (3) has substantially dampened the enthusiasm for further exploring retinoids for lung cancer treatment and prevention. The provocative article by Petty et al. (4) on a new retinoid receptor and retinoid resistance in lung cancer lights a spark that may help to rekindle interest in retinoids for cancer chemoprevention.
Retinoid effects, such as modulating cell growth, differentiation, and apoptosis, are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These receptors are members of the steroid hormone receptor gene superfamily, bind to the naturally occurring all-trans-RA (RARs) and 9-cis RA (RXRs), and are essential for the differentiation and maintenance of normal epithelium. RARs and RXRs each have three subtypes (,
, and
) with distinct amino- and carboxy-terminal domains (5). Disruption of the pathway of, and hence responsiveness to, retinoids may contribute to cancer development and account for the ineffectiveness of retinoids in preventing or treating lung tumors (6). Indeed, altered expression of nuclear retinoid receptors is associated with the malignant transformation of human cells. RAR
is the best-studied RAR subtype in the biology of retinoid effects on carcinogenesis and is the receptor subtype whose expression is most frequently decreased in lung cancer (7,8). Treatment with 9-cis-RA has been shown to restore RAR
expression, and thus potentially retinoid responsiveness, in the bronchial epithelium of former smokers (9), suggesting the restoration of homeostasis in this at-risk tissue. In stage I nonsmall-cell lung carcinoma (NSCLC) patients, however, a poorer prognosis is associated with tumors having a high expression of RAR
than with tumors not expressing RAR
(10). Furthermore, RAR
expression is directly associated with the expression of biomarkers such as COX-2 (in human NSCLC specimens) (11) and human telomerase reverse transcriptase (in the bronchial biopsies of smokers without cancer) (12) that are generally associated with a poor prognosis.
These clinical studies evaluated RAR expression as a monolithic entity and did not distinguish between the various RAR
isoforms that have been identified in humans. Differential expression of different RAR
isoforms, at least in part, probably underlie the apparently contradictory associations of RAR
expression in the clinical RAR
studies reported to date.
RAR has four isoforms that are generated differentially by means of the promoters P1 and P2 and alternative splicing. RAR
1 and RAR
3 are transcribed from the P1 promoter, and RAR
2 and RAR
4 from the P2 promoter. The three RAR
isoforms identified in humans are
1,
2, and
4 (5,13), and the importance of the distinct functions of these isoforms to the pathogenesis of lung cancer is just beginning to be elucidated. RAR
1/RAR
3 has been implicated in lung tumorigenesis in transgenic mice expressing antisense sequences to RAR
1/RAR
3 (14,15). RAR
1 is a fetal isoform not generally detected in normal tissues of adult humans, although it is expressed in small-cell lung cancer (16). Also, the expression of RAR
1 does not suppress the growth of NSCLC cells in vitro (15).
Petty et al. (4) have identified the novel RAR isoform RAR
1', which apparently is alternatively spliced from RAR
1 and is suppressed in association with retinoid resistance in lung carcinogenesis. RAR
1' expression was suppressed in RA-resistant lung cancer cell lines and in human lung cancer (compared with expression in adjacent histologically normal lung tissue). All-trans-RA and 5-azacytidine restored RAR
2, but not RAR
1', expression in retinoid-resistant lung cancer cells. However, exogenously expressed RAR
1' increased RA-dependent transcriptional activity and restored the ability of retinoids to suppress lung cancer cell growth and the expression of some, but not all, RA target genes. This elegant series of experiments by Petty et al. indicates that RAR
1' has biologic functions distinct from those of the previously known isoforms and may function as a tumor suppressor gene in the lung (4). Further studies to clarify the mechanisms of RAR
1' repression and potential reexpression in lung cancer may be important to future approaches to lung cancer chemoprevention.
RAR2 expression is also lost in lung tumorigenesis. Exogenously expressed RAR
2 enables RA to reduce the growth of lung cancer cells in vitro and in vivo. RAR
2knockout mice, however, do not develop lung cancer (17). RAR
2 expression is suppressed through methylation in lung carcinogenesis. RAR
4 is generated by alternative splicing from the same primary transcripts that generate RAR
2 and may be a dominant-negative form of RAR
2 that is overexpressed in lung and other cancer cell lines. RAR
4 transgenic mice spontaneously develop lung cancer (18).
The various isoforms of RAR have complex relationships and interactions that appear to influence lung carcinogenesis, as illustrated by studies in mice and humans. Transgenic mice expressing antisense RAR
1/RAR
3 develop lung cancer in association with increased RAR
2 and decreased RAR
4 expression (14). The ratio of RAR
4 to RAR
2 expression is increased in human lung cancers compared with that in normal cells (17), and reduced expression of RAR
2 is associated with the increased expression of RAR
4 in human esophageal cancer tissues (19).
Reviewing all the data from more than a decade of RAR research leads to the conclusion that different RAR
isoforms have different biologic functions in cancer development. RAR
1' and RAR
2 appear to have tumor suppressor activity (4,7,8). In contrast, RAR
4 appears to be oncogenic (18). The important functions of these RAR
isoforms in tumorigenesis will be further clarified in ongoing and future studies.
The resistance of lung carcinogenesis to retinoids is a complicated problem with roots in the complex pathogenesis of lung cancer, which likely involves the suppression of RAR2 expression (through epigenetic silencing via methylation or histone deacetylation) and of RAR
1' expression (through as yet unknown mechanisms) as well as other complex aberrations in RA signaling. Other mechanisms besides differential expression and functions of RAR
isoforms have also been postulated for the failure of retinoids in clinical lung cancer chemoprevention trials. Nevertheless, some important keys to understanding this failure may lie in new studies elucidating the distinct roles and regulation of various RAR
isoforms. The differential expression and effects of different RAR
isoforms are a potential area for molecular-targeted lung cancer chemoprevention, and targeting RAR
1' to overcome retinoid resistance would be one potentially promising new approach.
REFERENCES
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