Expression of the TSLC1 Adhesion Molecule in Pulmonary Epithelium and Its Down-Regulation in Pulmonary Adenocarcinoma Other than Bronchioloalveolar Carcinoma

Abstract

TSLC1 (tumor suppressor in lung cancer-1) is an adhesion molecule of the Ig superfamily that binds homophilically and mediates cell-cell interactions. Originally, TSLC1 was cloned as a candidate tumor suppressor from the genomic region that frequently exhibits loss of heterogeneity in human non-small-cell lung cancer (NSCLC). However, there have been no studies on TSLC1 expression in normal lungs or NSCLC. Here we show that pulmonary epithelial cells express TSLC1 and its expression levels are often decreased or lost in primary pulmonary adenocarcinoma, a major histologic type of NSCLC. Immunohistochemistry revealed that TSLC1 was localized at cell-cell boundaries of all columnar epithelial cells in mouse embryonic lungs of 10.5 and 13 days postcoitus. Similar staining patterns were observed in bronchiolar and alveolar epithelial cells of adult human lungs, suggesting a physiologic role for TSLC1 in interactions of these cells. Next we performed Western blot analyses of TSLC1 in 47 primary pulmonary adenocarcinomas and judged each tumor as either decreased or nondecreased by comparing TSLC1 expression levels of the tumor with the levels of normal lungs. The expression profiles had a significant relation to histologic subtypes but not to other clinicopathologic parameters. Sixteen bronchioloalveolar carcinomas (BACs) were all judged nondecreased, while 19 of 31 (63%) adenocarcinomas other than BAC were judged decreased (p < 0.0001). Immunohistochemistry of tumors judged nondecreased revealed that not only BAC cells but also tumor cells in lepidic growth components of adenocarcinomas other than BAC expressed TSLC1 on their lateral plasma membranes. These tumor cells are considered less invasive because they proliferate in a lepidic growth pattern along alveolar walls. Thus, the present results not only support the hypothesis that TSLC1 is a tumor suppressor of NSCLC but also suggest that preserved integrity of TSLC1 may contribute to less invasive phenotypes of lepidic growth tumor cells.

Expression of cell adhesion molecule 1 in malignant pleural mesothelioma as a cause of efficient adhesion and growth on mesothelium

“…In contrast, neither Meso-1 nor MeT-5A cells expressed CADM1 at all (Figure 2A). The variable mobility of CADM1 proteins detected among different cell lines can probably be attributed to post-transcriptional regulation, such as differential levels of glycosylation, as we previously reported in the lung 9 and liver. 10 Subcellular localization of CADM1 was examined by immunocytochemistry.…”

“…Similar characterizations of CADM1 have been reported in a variety of tumors, including non-small cell lung cancer 25 and nasopharyngeal carcinoma. 22 Because the cells of origin of these tumors, pulmonary and nasopharyngeal epithelial cells, 9,22 express the full-length form of CADM1, it has been postulated that the loss of CADM1 initiates the transformation of these cells into neoplastic cells. In contrast, MS-positive MPMs seemed to acquire CADM1 expression during or after the process of malignant transformation from mesothelial cells, because non-neoplastic mesothelial cells, even those with reactive atypia, did not express the full-length form of CADM1.…”

“…9 In MPMs and the lung parenchyma, two immunoreactive bands were detected at mobility sizes of 100 and 35 kDa (Figure 1h). We considered the larger band to represent the full-length form of CADM1 and the smaller its truncated form, as we described in mast cells.…”

“…9 Briefly, formalin-fixed, paraffinembedded tissues were cut into sections (4-mm thick) air-dried overnight at 371C deparaffinized in xylene, and rehydrated in a descending ethanol series. Endogenous peroxidase activity was blocked by immersion for 10 min in 0.3% hydrogen peroxide in methanol followed by a single wash in phosphate-buffered saline (PBS), pH 7.4.…”

“…8 Structurally, this adhesion molecule has three immunoglobulin-like motifs in the extracellular domain and a short cytoplasmic domain that interacts with other proteins via the protein 4.1-binding and PDZbinding motifs. 4,7 A variety of cells express CADM1, including epithelial cells, such as pulmonary and biliary epithelial cells, 9,10 and non-epithelial cells, such as neurons, 6 spermatogenic cells, 4,11 and mast cells. 12 CADM1 forms homodimers on the cell membrane through cis-interactions, and binds either trans-homophilically or heterophilically, depending on the cell type expressing the CADM1 and the binding partners available on adjacent cells.…”