Cadherin and catenin expression in normal human bronchial epithelium and non-small cell lung cancer

Abstract

Cadherins are transmembrane cell adhesion molecules (CAMS) that mediate cell–cell interactions and are important for maintenance of epithelial cell integrity. This function is dependent on an indirect interaction between the cytoplasmic domain of the cadherin molecule with three cytoplasmic proteins known as α-, β-, and γ-catenin (-cat). Growing evidence suggests that alterations in cadherin or catenin expression or function may be important to the development of an invasive or metastatic phenotype. Immunohistochemical techniques were used to study the expression of the two major epithelial cadherins, E-cadherin (E-cad) and P-cadherin (P-cad) as well as α- and γ-cat in normal bronchial epithelium and in a series of carefully TMN-staged pulmonary adenocarcinomas (n=21) and squamous cell carcinomas (n=7). The cadherin profile of normal pseudostratified bronchial epithelium was heterogeneous. Basilar cells strongly expressed P-cad, α- and γ-cat, while columnar cells moderately expressed E-cad, α- and γ-cat. In contrast to other epithelial tumors, E-cad on non-small cell lung carcinomas was actually upregulated, however, a decrease in P-cad expression was noted in 68%. At least one cadherin or catenin was downregulated, compared to normal bronchial epithelium, in 82% of tumors examined. With the exception of an association between loss of P-cad expression and poorly differentiated state, changes in cadherin and catenin expression levels were not significantly correlated to tumor stage, cell type, or nodal status. These findings illustrate that alteration of expression of cadherins and catenins are often found in non-small cell lung carcinoma when compared to the progenitor bronchial epithelium, and may play a role in the development of the malignant phenotype.

Introduction

Bronchogenic neoplasms are currently the most common cause of cancer mortality in the United States for both men and women, representing >170 000 deaths in yearly. Five-year survival rate with even local spread (hilar nodal disease—N1) is remarkably low, ∼30% at 5 years [1]. In addition, 30–40% of patients without evidence of nodal disease at resection (NO) eventually die from metastatic spread. It would thus be useful to have more reliable prognostic indicators at the time of tumor resection. In addition, a better understanding of changes in tumor cell biology that results in a more aggressive neoplastic phenotype may lead to the development of more effective therapeutic modalities.

Although the loss of cell–cell adhesion and invasion of carcinoma cells into the surrounding mesenchymal tissue has been associated with the malignant phenotype for more than 50 years, only recently have the molecular components responsible for these changes been identified. One important area of research has been the characterization of cell–cell and cell–substratum adhesion molecules. Alterations in immunoglobulin superfamily members and the cadherins have been noted in tumor progression [2]. The authors have previously examined the distribution of cell–substratum adhesion receptors (integrins) on non-small cell lung (NSCL) cancer tissues [3], [4]. Integrin expression was somewhat heterogeneous; however, the tumors tended to express fewer integrins than did normal bronchial tissue. These findings have been corroborated in a much larger study of over 60 tumors [5].

In this study, the authors examined a group of lung cancer specimens with regard to expression of important cell–cell adhesion molecules, namely the cadherins and the cadherin-associated proteins, the catenins. Cadherins are a class of calcium-dependent transmembrane cell adhesion molecules (CAMs) that mediated cell–cell interactions via homophilic interactions and are important in the maintenance of epithelial cell integrity [6], [7]. This function is dependent on an indirect interaction between the cytoplasmic domain of the cadherin molecule with the cytoskeleton mediated via three cytoplasmic proteins known as α-, β-, and γ-catenin (-cat) [7], [8], [9] that form a complex with the cadherin molecule.

A growing body of evidence suggests that alternations of cadherin or catenin expression or function may be important to the development of an invasive or metastatic phenotype [10]. Work using cultured cells has shown that decreased E-cadherin (E-cad) expression correlated with tumor cell ‘invasiveness’ and that cell lines with little endogenous adhesive ability gained the adhesive (non-invasive) phenotype after transfection with exogenous E-cad cDNA [11], [12], [13], [14]. Although the correlation between loss of E-cad expression and invasive properties is well established in experimental systems, the relationship of E-cad expression in actual tumor specimens (as assessed by immunohistochemical techniques) with metastasis, cell dedifferentiation, and decreased survival rate is more complex and appears to be somewhat tumor-specific. For example, a clear inverse correlation between immunohistochemical expression of E-cad and tumor dedifferentiation and patient survival rates has been demonstrated in squamous cell carcinomas of the head and neck [15], [16], esophageal cancer [17], [18], prostate cancer [19], [20], and bladder tumors [21], [22]. In studies examining other tumor types such as colon, breast, and gastric carcinoma these correlations have been less definitive, with some studies indicating a clear link between loss of cadherin expression and malignant phenotype [23], [24], [25], [26], [27] and others not [28], [29], [30]. The expression of other cadherins, and of catenins, in cancer has been not well studied, however, preliminary data suggests that downregulation of P-cadherin (P-cad) and α-cat is associated with at least some malignancies [30], [31], [32], [33].

Very little is known about the expression of cadherins and catenins on normal or malignant bronchial epithelium, however, as discussed above, data from other types of tumor suggest that loss of cadherin and/or catenin expression might correlate with the degree of differentiation or propensity for lymph node metastasis and thus provide a useful marker for patients at high risk of metastatic disease. The purpose of this study was to examine the expression of these molecules in a large series of well-characterized lung carcinomas in which careful mediastinal lymph node staging had been performed. The authors have therefore used immunohistochemical techniques to identify the two major epithelial cadherins, E-cad and P-cad, as well as α- and γ-cat in normal bronchial epithelium and both pulmonary adenocarcinomas (n=21) and squamous cell carcinoma (n=7). This information was then correlated to the histologic type of tumor, the degree of differentiation, and the presence of lymph node metastasis.