Elsevier

Lung Cancer

Volume 42, Issue 2, November 2003, Pages 195-202
Lung Cancer

Expression of caveolin-1 is associated with poor prognosis of patients with squamous cell carcinoma of the lung

https://doi.org/10.1016/S0169-5002(03)00287-3Get rights and content

Abstract

Background: Caveolin-1, as a major component of caveolae, is involved in the regulation of cell cycle by impacting various signaling pathways. Previous studies of caveolin-1 in cancer showed two contrary results. In most in vitro studies, caveolin-1 played a role as a tumor suppressor. On the other hand, the elevated expression of caveolin-1 was often reported to be associated with poor clinical outcome in human studies. These results indicate differential biological functions of caveolin-1 depending on the development and progression stage of cancer in vivo. Methods: To clarify the correlation between the clinicopathologic profiles of pulmonary squamous cell carcinomas and the expression of caveolin-1, 107 cases of formalin-fixed and paraffin-embedded tissues of pulmonary squamous cell carcinomas were immunohistochemically evaluated for the expression of caveolin-1 by the tissue-array method. Results: Caveolin-1 was expressed in 34 cases (31.7%) among 107 cases of pulmonary squamous cell carcinoma. The expression of caveolin-1 was statistically correlated with pathologic stage (stage I and II vs. III; P<0.001), pT (T1 and T2 vs. T3 and T4; P=0.001), and pN (N1 vs. N2 and N3; P=0.0143). The patients with caveolin-1 expression in pulmonary squamous cell carcinomas showed a poorer prognosis than those in caveolin-1-negative group (P=0.0345). Conclusion: The expression of caveolin-1 is significantly correlated with advanced pathologic stage and poor prognosis in pulmonary squamous cell carcinoma. The results of current study suggest that the expression level of caveolin-1 may be a candidate factor for predicting prognosis in patients with pulmonary squamous cell carcinoma.

Introduction

Lung cancer is the leading cause of cancer deaths in most industrialized countries as well as Korea. Squamous cell carcinoma of the lung, a common malignant tumor with poor prognosis, accounts for one-thirds of primary lung cancer. Prognosis of patients with pulmonary squamous cell carcinomas is mainly dependent on the stage of the disease. However, even in patients with stage I of squamous cell carcinoma, the 5-year survival rate is 50% [1]. For the precise prognosis of the squamous cell carcinoma of the lung, the development of biological markers that have high prognostic correlation with various cancer stages is necessary. Although many investigators have been trying to identify biological markers for the pulmonary squamous cell carcinoma, so far, there are only few prognostic parameters that make possible to estimate the average surviving time of patients with squamous cell carcinoma of the lung.

Caveolin-1, the principal structural protein in caveolae, has been recognized as a key player in the regulation of several signal transduction molecules, such as the HARS protein, epidermal growth factor (EGF) receptor, Src family tyrosine kinase, protein kinase C, transforming growth factor β/SMAD, and the Wnt/beta-catenin/lef-1 pathway [2], [3], [4], [5], [6]. Caveolin-1 has been also reported to be a negative regulator of inducible nitric oxide synthase (iNOS), [7] which could induce anti-tumor effect through inflammatory reaction. Three members of caveolin gene family have been cloned: caveolin-1 (of which there are two isoforms, α and β), caveolin-2, and caveolin-3 [8], [9], [10]. Among them, caveolin-1 is an interesting molecule due to its paradoxical biological functions in malignant tumors. Decreased expression of caveolin-1 has been found in a variety of cancer cell lines of breast carcinoma, lung carcinoma, colon carcinoma, uterine cervical carcinoma, and sarcoma [11], [12], [13], [14], [15]. Overexpression of recombinant caveolin-1 inhibited tumor cell growth in breast cancer cell lines and decreased colony formation of sarcoma cells [11], [15]. Moreover, it was observed that oncogenic overexpression of src, v-abl, and Ha-ras resulted in reducing expression of caveolin-1 [16], [17], [18]. Based on these results, it has been suggested that caveolin-1 may play a role as a tumor suppresser. Conversely, overexpression of caveolin-1 was also observed in many human cancer tissues; breast carcinoma, prostate carcinoma, ovarian carcinoma, esophageal squamous cell carcinoma, and papillary carcinoma of the thyroid [19], [20], [21], [22], [23].

In the study of prostate carcinoma [20], elevated caveolin-1 protein levels were associated with cancer progression and decreased patients’ survival rate. However, it is not known whether the expression level of caveolin-1 in squamous cell carcinoma of the lung is related to tumor progression and prognosis. Thus, in this study we focused the elucidation of the relationship between the expression of caveolin-1 in pulmonary squamous cell carcinoma and clinical information such as survival data obtained retrospectively.

Section snippets

Patients and samples

A total of 107 patients with primary pulmonary squamous cell carcinoma undergoing surgical resection (34 pneumonectomies, 73 lobectomies) between 1 January 1995 and 30 June 2000 at the Department of Pathology, Seoul National University College of Medicine (Seoul, Korea) were included in current retrospective study. The patients with tumor metastasis to other organs and/or separate tumor nodule(s) in a different lobe, and secondary operation were excluded. Each tumor was reevaluated with regard

Clinical findings

Cases of 107 patients (96 men, 11 women) with a mean age of 62 years (range 41–81) were examined. A relatively large number of patients had the onset age of tumor at more than 60 years (66 patients, 61.7%). The mean follow-up period was 27.5 months (from 25 days to 66.1 months). Pathological staging was performed according to the TNM classification of the International Union Against Cancer. Eighteen patients were at Stage IA, 39 patients at Stage IB, eight patients at Stage IIA, 20 patients at

Discussion

Since caveolin-1 was first identified in 1989 by Glenney, [24] as a major v-Src substrate in Rous sarcoma virus-transformed chicken embryo fibroblasts, its major functional role of caveolin-1 in malignant tumors has been suggested as a tumor suppressor based on in vitro and in vivo data. However, several reports published recently demonstrated that overexpression of caveolin-1 is associated with poor prognosis in prostate carcinoma and esophageal squamous cell carcinomas [20], [22]. Thus,

Acknowledgements

This study is supported in part by a grant from DiNonA Inc. The authors are grateful to Dr Seong Hoe Park for his support of this project and also thank Dr Im-Soon Lee for critical review of manuscript.

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