Elsevier

Lung Cancer

Volume 59, Issue 3, March 2008, Pages 340-349
Lung Cancer

ALDH1A1 and ALDH3A1 expression in lung cancers: Correlation with histologic type and potential precursors

https://doi.org/10.1016/j.lungcan.2007.08.033Get rights and content

Summary

We hypothesize that aldehyde dehydrogenase (ALDH) isozymes may be upregulated in lung tissue as a result of exposure to carcinogenic aldehydes found in cigarette smoke. To investigate this hypothesis, we studied the expression of two ALDH isozymes in lung cancer from patient samples and its relationship to the history of cigarette smoking. Immunohistochemical staining for ALDH1A1 and ALDH3A1 was performed on archival specimens from control patients without lung cancer, and patients with one of the primary lung cancers: squamous cell cancer (SCCA), adenocarcinoma (AdenoCA), and small cell lung cancer (SCLC). An overall score was obtained for each sample based upon multiplying the staining intensity (0–3) and the extensiveness (0–100%). Mean ± S.E.M. for each experimental group was calculated and compared. Our results indicate a significantly higher level of expression of ALDH1A1 and ALDH3A1 in SCCA (155 ± 19 and 162 ± 17, respectively) and AdenoCA (116 ± 12 and 107 ± 10) than SCLC (39 ± 11 and 42 ± 12) (P < 0.01). Atypical pneumocytes demonstrated significantly higher levels of expression of ALDH1A1 and ALDH3A1 than normal pneumocytes (a normal counterpart of AdenoCA), which is suggestive of up regulation during malignant transformation to AdenoCA. A subset analysis of all samples studied revealed increased expression of ALDH1A1 (P = 0.055) and ALDH3A1 (P = 0.0093) in normal pneumocytes of smokers (n = 32) in comparison to those of non-smokers (n = 17). Non-small cell lung cancer (NSCLC) express very high levels of ALDH1A1 and ALDH3A1 in comparison with SCLC, elevated expression of both enzymes may be associated with malignant transformation to AdenoCA, and cigarette smoking seems to result in increased expression of these enzymes in normal pneumocytes.

Introduction

Although lung cancer is responsible for the greatest number of cancer-related deaths in both sexes in the United States, the processes involved in pulmonary carcinogenesis are not well understood. About 85% of lung cancer cases are attributed to cigarette smoking and it is well documented that tobacco smoke contains more than 50 carcinogens including carcinogenic aldehydes such as acetaldehyde and acrolein [1], [2], [3], [4], [5], [6], [7], [8], [9].

Aldehyde dehydrogenases (ALDHs) are a family of intracellular enzymes that catalyze the oxidation of a variety of aldehydes [10], [11], [12]. Two isozymes, cytosolic class 1A1 (ALDH1A1) and class 3A1 (ALDH3A1), have been shown to play a role in drug resistance [13], [14], [15], [16]. Several studies have determined that overexpression of ALDH1A1 and ALDH3A1 in cell lines confers resistance in vitro to oxazaphosphorines, including cyclophosphamide and its metabolites [17], [18], [19], [20], [21], [22]. We have also previously shown that reducing expression of ALDH1A1 by using antisense RNA or siRNA and/or all-trans retinoic acid increases the in vitro sensitivity of tumour cells to 4-hydroperoxycyclophosphamide, an active metabolite of cyclophosphamide (CP) [23], [24], [25]. Other investigators have reported the protective effects of ALDH3A1 against UV radiation and hydroxynonenal induced cellular damage as well as against the toxicity of mitomycin-C and VP-16 [26].

ALDH1A1 and ALDH3A1 were reported to be highly expressed in non-small cell lung cancer (NSCLC) cell lines [27], but have not been studied in normal and neoplastic human lung tissues. Considering the different metabolic activities of these enzymes, we presumed that their overexpression contributes to the overall drug resistance phenotype that usually characterizes the different types of NSCLC. Because of the possible involvement of these enzymes in the detoxification of carcinogenic aldehydes, the association of tobacco smoke and the development of lung cancer, and the presence of many carcinogenic aldehydes in tobacco smoke, we hypothesized that ALDH1A1 and ALDH3A1 may be upregulated in both normal and malignant lung tissues of cigarette smokers. In this study, we investigated the expression of ALDH1A1 and ALDH3A1 in normal lung tissues, non-small cell and small cell lung cancers, and preneoplastic epithelial lesions, as well as evaluated the relationship between cellular enzyme expression and tobacco smoking status.

Section snippets

Patients and samples

Approval to conduct this investigation was obtained from the University of Florida Institutional Review Board, and the study was exempted from the requirement of informed consent. The surgical pathology files at Shands Hospital at the University of Florida were searched for cases of non-small cell carcinomas, small cell carcinomas, and histologically benign lung samples to be used as controls. Cases were retrieved as follows: adenocarcinomas (AdenoCa) (n = 19), squamous cell carcinomas (SCCA) (n = 

Results

Eighty-eight subjects were included in this study, and their characteristics are summarized in Table 2. Three different experimental groups and one control group were analysed and compared. The control group includes patients without primary lung cancer as well as smokers and non-smokers. Although for the most part the groups were similar, some significant differences were revealed between some of the experimental groups when compared to the control. Mainly and as expected, the control group

Discussion

Most data on ALDH1A1 and ALDH3A1 comes from studies using lung cancer cell lines and animal studies [36]. Because of our interest in these enzymes as targets for therapeutic intervention, we conducted this study for the main purpose of establishing the pattern of expression of these enzymes in actual patient specimens from common types of lung cancer. Our results have confirmed that two types of NSCLC, AdenoCA and SCCA, express high levels of ALDH1A1 and ALDH3A1, while SCLCs express low levels

Conflict of interest

None.

Acknowledgement

Financial support for this work was provided by a grant (to JSM) from the Flight Attendant Medical Research Institute (Miami, FL).

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