ReviewVitamin A/retinoids signalling in the human lung
Introduction
Despite tobacco smoking prevention, lung cancer remains the number 1 cause of cancer-related deaths in developed countries [1]. In the absence of early diagnosis tools, the prognosis is poor. However, epidemiological observations and positive laboratory findings had generated hope for the use of vitamin A/retinoids (Vit A) in lung cancer chemoprevention for high-risk individuals.
Indeed, (A) there is a consistent inverse association between the intake of fruits and vegetables containing pro-Vit A (carotenoids) and the risk of lung cancer [2]. (B) There is also a similarity between the bronchial lesions found in carcinogen-treated animals (squamous metaplasia) and the histological changes affecting the bronchial epithelia of humans or animals deficient in Vit A. Restoration to a normal histological aspect occurs after Vit A repletion, which also confers protection against pro-carcinogens like benzo[a]pyrene in experimental models [3]. (C) In addition, smokers present more squamous metaplasia than non-smokers [4] and the multistep process leading to squamous cell lung carcinoma (SQCLC) also begins by squamous metaplasia [5]. (D) Early studies have shown that retinoids decreased the incidence of overall second primaries in patients with head and neck cancers [6]. All-trans retinoic acid (at-RA) was efficient to reverse pre-neoplastic oral lesions and to enhance the regression of cervical intraepithelial neoplasia [7].
In this promising context, in the middle 1980s, lung cancer chemoprevention trials with Vit A/retinoids began. Etretinate was found able, in small uncontrolled studies, to reverse bronchial squamous metaplasia in chronic smokers [4] but controlled trials in the 1990s, failed to confirm these results [8]. In the mean time, large primary prevention trials against smoking-related tumors began. Four have now been completed and have reported striking increases in lung cancer incidence, pointing even to β-carotene as a potent human carcinogen: see the α-tocopherol, β-carotene trial with or without β-carotene in the retinol efficacy trial, the physician's health study with or without β-carotene and recently the EUROSCAN trial results after retinyl palmitate and/or N-acetyl cystein supplementation in high-risk individuals [9], [10], [11], [12], [13].
The relative simple chemical structure of Vit A/retinoids had allowed for the development of numerous synthetic retinoids and as early as 1976, M. Sporn group used Vit A-deprived hamster tracheal rings in culture as a simple model of bronchial squamous metaplasia to test Vit A and its synthetic derivatives in their ability to restore a normal bronchial epithelium [14]. A body of other studies have shown that Vit A/retinoids play a major role in the growth, death and differentiation of embryonic and adult normal or abnormal tissues. The most dramatic anti-tumor effect was shown by at-RA in acute promyelocytic leukaemia [15]. Consequently, some derivatives have been tested in vivo to treat advanced lung tumors as alternative approaches to intensive cytotoxic chemotherapy. Overall, few objective responses have been reported in metastatic non-small cell lung cancers (NSCLCs) pre-treated with chemo and/or radiotherapy when combining α-interferon and at-RA [16].
The discovery of nuclear receptors for retinoids: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) greatly enhanced our understanding of retinoid signalling [17]. Specific knock-out mice have been generated to dissect the role of each gene during embryogenesis [18] and synthetic retinoids specific for a given RAR or a given RXR as well as novel retinoids able to overcome RA resistance in several NSCLC cell lines have been synthesised [19]. RARs selective retinoids are generally more active to slow cell growth than RXRs selective retinoids. However, at suboptimal concentrations, RAR agonists synergise with RXR agonists to inhibit malignant cell proliferation. In rabbit tracheal epithelial cells primary cultures: RARα and β agonists or RAR panagonists were required to inhibit squamous metaplasia but RARγ agonists only induced growth arrest and apoptosis of basal proliferative cells [20]. In human bronchial epithelial cells, RA and RARs selective retinoids but not RXRs, inhibited squamous differentiation and induced CYP26 mRNA whose defective regulation could explain inadequate RA catabolism [21].
Evidences have accumulated pointing to the prominent role of the RARβ gene in lung cancer and will be reviewed. Future research for lung cancer chemoprevention could use the new retinoids, but without a better scientific understanding of the basic biological mechanisms of Vit A/retinoids signalling in the lung it would be unethical. With this purpose, we review what is known about Vit A/retinoids signalling, restricting our scope mainly to the human lung, adopting simplifications for an easy reading by all concerned physicians and listing only key references, which contain further relevant references.
Section snippets
Vitamin A/retinoids
Chemical compounds belonging to the Vit A family, as defined by the International Union of Pure and Applied Chemistry/International Union of Biology Joint Commission on Biochemical Nomenclature, have a structure based on four isoprenoid units joined in a head-to-tail manner to produce a monocyclic parent having five carbon–carbon double bonds and a functional group at the acyclic terminus [22]. The typical parent compound is all-trans retinol (at-retinol).
Both plants and animals are dietary
Retinoids receptors
In addition to their role in chemoprevention and malignant transformation, Vit A/retinoids play crucial roles in a wide variety of biological processes including embryo morphogenesis and cell homeostasis: proliferation and differentiation. Retinoids exert these pleiotropic effects through two classes of nuclear ligand-dependent transactivators, the RARs, which are activated by at-RA and its 9-cis isomer, and the RXRs activated by 9-cis RA only. There are three RARs (α, β, and γ) and three RXRs
Retinoids and lung development
The human respiratory system is not operative until birth and develops until puberty. During the fourth week of foetal development, the caudal part of the laryngotracheal groove (pharynx) forms a tube of endoderm, which will differentiate into the epithelial cells and glands of the trachea to give the bronchial tree. In parallel, cells from the splanchnic mesoderm surround this respiratory tube and form the connective tissue of the respiratory system. Two initial bronchial buds separate and
Retinoids receptors knock-out mice
In order to assess the functions of RR genes and isoforms during normal embryogenesis, specific knock-out mice have been engineered [38]. RARα−/− and RARγ−/− mice showed several symptoms of the post-natal RA deficiency syndrome: lethality, poor weight gain and male sterility, which could all be cured or prevented by RA supplementation. RARβ−/− displayed persistent retro-lenticular membrane. Single RAR null mutant mice developed almost normally, indicating that some degree of functional
Retinoids receptors in lung cancer
It was discovered first that many lung cancer cell lines carry large non-random 3p14–25 deletions [52]. Then Houle et al. mapped the RARβ gene at 3p24 and demonstrated that RARβ expression was decreased [53] or even suppressed in lung cancer cell lines, suggesting that its re-expression could suppress malignity. This idea was reinforced when reintroduction of the RARβ gene into lung cancer cells suppressed their tumorogenicity in nude mice and when transgenic mice expressing antisens RARβ2 RNA
Retinoids receptors and bronchial precursor lesions
The sequence of events in the development of squamous carcinoma in the large airway is that carcinogens such as those contained in tobacco smoke lead to a series of morphologic and genetic changes [58], which ultimately lead to carcinoma. These changes include basal cell hyperplasia and squamous metaplasia, which are thought to be reversible, followed by varying degrees of dysplasia and ultimately by carcinoma in situ. The marked and frequent down-regulation of several RARs/RXRs in invasive
Discussion
In experimental animal models of epithelial cancers, Vit A/retinoids were reported to suppress the malignant phenotype induced by chemical or physical carcinogens. They appeared most effective during the late tumor promotion phase [60]. But opposite results were also reported in high-risk individuals and were attributed to variations in retinol basal levels. In smokers, although reexpression of RARβ mRNA after 13-cis RA was observed in the bronchial mucosa there was no regression of squamous
Conflict of interest statement
Authors have no conflict of interest to disclose.
Acknowledgements
This work was supported in part by grants of: the Ligue Lorraine Contre le Cancer, the European contract “Early Lung Cancer Detection” QLRT 200101735, the contract no. 2002 for Clinical Research from the Centre Hospitalier Régional of Nancy and the Cancéropole Grand Est.
References (62)
- et al.
Mortality from tobacco in developed countries: indirect estimation from national vital statistics
Lancet
(1992) Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention
Lancet Oncol
(2002)- et al.
Degree of bronchial metaplasia in heavy smokers and its regression after treatment with a retinoid
Lancet
(1982) - et al.
Cloning, gene organization and identification of an alternative splicing process in lecithin:retinol acyltransferase cDNA from human liver
Gene
(2004) - et al.
Isolation and characterization of a microsomal acid retinyl ester hydrolase
J Biol Chem
(2005) - et al.
Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination
J Biol Chem
(1995) - et al.
Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family
Mol Aspects Med
(2003) - et al.
Related enzymes solve evolutionarily recurrent problems in the metabolism of carotenoids
Trends Plant Sci
(2005) - et al.
The nuclear receptor superfamily: the second decade
Cell
(1995) - et al.
Nuclear retinoid receptors and the transcription of retinoid-target genes
Gene
(2004)
The expression of nuclear retinoid receptors in human implantation
Placenta
Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes
Adv Cancer Res
Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration: a review of recent research
Nutr Rev
Experimental cancer of the lung. Inhibition by vitamin A of the induction of tracheobronchial squamous metaplasia and squamous cell tumors
Cancer
Regression of bronchial epidermoid metaplasia in heavy smokers with etretinate treatment
Cancer Detect Prev
Prevention of second primary tumours with isotretinoin in squamous-cell carcinoma of the head and neck
N Engl J Med
Retinoids in lung cancer prevention and treatment
Ann Oncol
Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia
J Clin Oncol
Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial
J Natl Cancer Inst
Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease
N Engl J Med
EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups
J Natl Cancer Inst
Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids)
Fed Proc
Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid)
N Engl J Med
13-cis-Retinoic acid plus interferon-alpha: a phase II clinical study in squamous cell carcinoma of the lung and the head and neck
Oncology
A decade of molecular biology of retinoic acid receptors
FASEB J
Principles for modulation of the nuclear receptor superfamily
Nat Rev Drug Discov
Identification of receptor-selective retinoids that are potent inhibitors of the growth of human head and neck squamous cell carcinoma cells
Clin Cancer Res
Differential effects of several retinoid receptor-selective ligands on squamous differentiation and apoptosis in airway epithelial cells
Cell Tissue Res
Induction of the cytochrome P450 gene CYP26 during mucous cell differentiation of normal human tracheobronchial epithelial cells
Mol Pharmacol
The importance of vitamin A in nutrition
Curr Pharm Des
Cited by (23)
Quantitative proteomics analysis of differentially expressed proteins in ruptured and unruptured cerebral aneurysms by iTRAQ
2018, Journal of ProteomicsCitation Excerpt :These properties suggested that S100A9 could be an important moderator of aneurysms and may be a possible target for therapy against human intracranial aneurysms. Cellular retinoic acid-binding protein 1 (CRABP1) is a small cytosolic protein encoded by CRABP1 gene and it plays a dominant role in the modulation of retinoic acid (RA) signaling pathway [47]. Because of the potential role of RA in regulating cell growth and differentiation, retinoic acid and retinoid receptors expression have been reported to be associated with initiation and progression of several human tumors [48].
Chromosome mapping, expression and polymorphism analysis of CRABP1 gene in pigs
2014, Journal of Integrative AgricultureA new approach to highly sensitive determination of retinoic acid isomers by preconcentration with CdSe quantum dots
2014, TalantaCitation Excerpt :Retinoic acid (RA) is the bioactive metabolite of vitamin A (retinol), which acts in the all-trans, the 13-cis, the 9-cis and the 9,13-di-cis isomer forms – each with unique function [1–3] (Fig. 1). In vertebrates and their embryos developing under unusual amounts of RA conditions, a wide range of abnormalities have been described; including defects of the central nervous system, eye, face, dentition, ear, limb, urogenital system, lungs, heart and aortic arch defects [4–13]. Based on the previous studies, present of RA isomers in many tissues and plasma confirms the RA critical role in vertebrates [14–26].
Thymoquinone Crosstalks with DR5 to Sensitize TRAIL Resistance and Stimulate ROS-Mediated Cancer Apoptosis
2021, Asian Pacific Journal of Cancer PreventionVitamin A: Roles in oxidative stress, inflammation and obesity
2021, Vitamin A: Nutrition, Side Effects and SupplementsNutrition and cancer
2020, Handbook of Research on Advancements in Cancer Therapeutics