E-Cadherin–-Catenin Adhesion Complex in Neuroendocrine Tumors of the Lung: A Suggested Role Upon Local Invasion and Metastasis C. SALON, MD, D. MORO, MD, S. LANTUEJOUL, MD, PHD, P. Y. BRICHON, MD, PHD, H. DRABKIN, MD, PHD, C. BRAMBILLA, AND E. BRAMBILLA, MD, PHD Dysfunction or loss of the intercellular adhesion complex E-cad- herin–-catenin is frequent in non–small cell lung carcinomas in which E-cadherin and -catenin loss has been considered to be a molecular marker of tumor progression and poor prognosis. With an aim of evaluating the expression of the E-cadherin–-catenin com- plex and its prognostic role in neuroendocrine tumors (NET) of the lung, immunohistochemical analysis was performed in 102 NET, including 16 low-grade typical carcinoids, 8 intermediate-grade atyp- ical carcinoids, 37 large-cell neuroendocrine carcinomas (LCNEC), and 41 small-cell lung carcinomas, both high-grade tumors. Impaired E-cadherin expression (loss or cytoplasmic delocalization) was ob- served in 80 (78%) of 102 samples, and impaired -catenin expres- sion was noted in 74 (72%) of 102 cases. The impaired expression of E-cadherin and -catenin was observed with a higher frequency in high-grade tumors (87% and 83%, respectively) than in carcinoids (50% and 37%, respectively; P < 0.0001). Impaired expression of the E-cadherin and -catenin molecules also correlated with lymph node metastasis (P  0.0001 and P  0.0005, respectively) and with ad- vanced stage disease (P < 0.0001 for both factors). Moreover, im- paired E-cadherin expression directly correlated with an extensive disease in carcinoids and in LCNEC (P  0.02 and P  0.04, respec- tively) and with node metastasis in LCNEC (P  0.01). Levels of E-cadherin and -catenin were correlated with each other, consistent with an internal regulatory loop. Our results indicate that down- regulation of the E-cadherin–-catenin complex plays a role in NET progression. HUM PATHOL 35:1148-1155. © 2004 Elsevier Inc. All rights reserved. Key words: neuroendocrine tumors, lung cancer, E-cadherin, -catenin. Abbreviations: TC, typical carcinoid; AC, atypical carcinoid; LCNECs, large-cell neuroendocrine carcinomas; SCLC, small-cell lung carcinomas. The invasive growth of tumor cells and tendency to metastasize are major impediments to curative surgical resections. In carcinomas, disruption of intercellular adhesion is one of the crucial steps in invasive growth processes in which various cell adhesion molecules play an important role. Among them, the transmembrane glycoprotein E-cadherin, a member of the cadherin family that mediates homotypic calcium-dependent cell– cell adhesion, plays a critical role in carcinogenesis and in tumor invasion. 1 Several in vitro studies have suggested an invasion suppressor role for E-cadherin. 2-4 Moreover, this factor is targeted in vivo for inactivation by several means, including mutation and deletion in the gene encoding E-cadherin, 5,6 methylation and tran- scriptional suppression of its promoter, 7 and posttrans- lational alteration leading to its cytoplasmic redistribu- tion 8 and loss of the adhesive properties of E-cadherin pathway. -Catenin is a cytoplasmic protein that interacts directly with E-cadherin and links this molecule to the actin cytoskeleton via -catenin. 9 -Catenin, as a key component of intercellular adhesion junctions, plays a critical role in E-cadherin–mediated adhesion. The full adhesive function of E-cadherin depends on the integ- rity of the entire E-cadherin– catenin–actin network. Various morphological studies have shown a correla- tion between E-cadherin down-regulation, loss of dif- ferentiation, tumor aggressiveness, and metastasis. 1,10 In addition, free cytoplasmic -catenin can enter the nucleus and function as a transcriptional activator. This was initially discovered for the wingless (wnt) pathway, but other transcription factors (eg, VDR, RAR, AR) can also be activated by -catenin. 11-13 In non–small cell lung cancer cell lines, WNT–- catenin signaling leads to up-regulation of E-cadherin, as it does in Drosophila. 14 In contrast, in colorectal can- cer, various mutations lead to up-regulation of -cate- nin and activation of TCF/LEF target genes (eg, MYC, cyclin D1). 15 In lung cancer, loss of E-cadherin or -catenin has been associated with a poor survival. This was most notable in squamous cell carcinomas, and the significance of E-cadherin and -catenin loss in other subtypes is less clear. 16,17 Here we report the first analysis of the E-cadherin– -catenin complex in the spectrum of neuroendocrine tumors of the lung. The recent (1999) World Health From the Laboratory of Cellular Pathology and the Department of Thoracic Oncology, INSERM U578: Molecular Basis of Lung Can- cer Progression, University Hospital, Grenoble, France; and the Di- vision of Medical Oncology, B-171, University of Colorado Health Sciences and Cancer Centers, Denver, CO. Accepted for publication April 22, 2004. Supported by grants from Association pour la Recherche contre le Cancer, La Ligue Contre le Cancer, French Health Ministry (H.D. and R.G.) and by a Lung Cancer Specialized Program of Research Excellence grant (National Institutes of Health CA58187). Address correspondence and reprint requests to E. Brambilla, MD, PhD, Laboratory of Cellular Pathology, University Hospital, 38000 Grenoble, France. 0046-8177/$—see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2004.04.015 1148