Elsevier

Lung Cancer

Volume 66, Issue 1, October 2009, Pages 1-7
Lung Cancer

Review
Vitamin A/retinoids signalling in the human lung

https://doi.org/10.1016/j.lungcan.2009.03.008Get rights and content

Abstract

Vitamin A is used as a generic term for all vitamin A derivatives with retinol-like biological activity. Retinol is the main parent compound for vitamin A. It derives from carotenoids (provitamin A) and also directly from the pre-formed vitamin A contained in the diet. The term “retinoid” is a generic descriptor of compounds structurally related to vitamin A and the synthetic analogues of retinol with or without biological activity. Retinoic acid is the active cellular catabolite. Vitamin A/retinoids have been given cancer-preventive functions and subsequently used in clinical trials to reduce lung cancer incidence in high-risk individuals. The results obtained have been in contradiction with both in vivo and in vitro promising studies. It seems therefore necessary to develop a better understanding of the vitamin A/retinoids signalling pathways in the lung. With this aim, we summarise the relevant knowledge focussed on the 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.

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