Expression of e-cadherin, α-catenin, β-catenin, and CD44 (standard and variant isoforms) in human cholangiocarcinoma: An immunohistochemical study

✍ Scribed by Keigo Ashida; Tadashi Terada; Yukisato Kitamura; Nobuaki Kaibara

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 237 KB
• Volume: 27
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510270412

✦ Synopsis

Immunolocalization of E-cadherin (E-cad), ␣-catenin, ␤-catenin, and CD44 has rarely been investigated in human cholangiocarcinoma (CC). We, therefore, immunohistochemically examined the expression of E-cad, ␣-catenin, ␤-catenin, CD44 standard (CD44s), and CD44 variants (CD44v) including CD44v5, CD44v6, CD44v7-8, and CD44v10 in normal adult livers and in 47 cases of CC; and the results were then correlated with tumor grade, vascular invasion, metastasis, p53 expression, proliferative fraction (Ki-67 labeling), and c-erbB2 expression. In normal livers, E-cad, ␣-catenin and ␤-catenin, but not CD44s, CD44v5, CD44v6, CD44v7-8, and CD44v10, were expressed at the cell membrane of normal intrahepatic bile ducts. In CC, membranous expression of E-cad, ␣-catenin, and ␤-catenin was the same or reduced when compared with noncancerous bile ducts in the majority of CC. We found that the down-regulation of E-cad, ␣-catenin, and ␤-catenin expression significantly correlated with tumor high grade, but not with vascular invasion, metastasis, p53 expression, Ki-67 labeling, or c-erbB2 expression, except for ␤-catenin, the down-regulation of which was associated with c-erbB2 down-regulation. CD44s, CD44v5, CD44v6, CD44v7-8 and CD44v10 were frequently expressed at the membrane of CC cells. There were, however, no significant correlations between these aberrant CD44 expression and tumor grade, metastasis, vascular invasion, p53 expression, Ki-67 labeling, or c-erbB2 expression, with a few exceptions of CD44s and CD44v5. We found that CD44s aberrant expression significantly correlated with absence of metastasis and vascular invasion, and that CD44v5 aberrant expression significantly correlated with p53 under-expression. These results suggest that membranous expression of E-cad, ␣-catenin, and ␤-catenin is reduced in a majority of CC and this down-regulation correlates with CC high grade, and that ␤-catenin down-regulation is associated with c-erbB2 down-regulation. The data also suggested that CD44s, CD44v5, CD44v6, CD44v7-8, and CD44v10 may be neoexpressed during carcinogenesis of CC but this neoexpression does not correlate with tumor progression in CC, with the exception of CD44s and CD44v5. (HEPATOLOGY 1998;27:974-982.)

Cell-to-cell and cell-to-matrix adhesion is critical to the establishment and maintenance of normal tissue architecture. 1,2 It is achieved by a number of molecules, collectively termed ''cell adhesion molecules'' (CAMs). 1,2 The CAMs consist of five relevant families, i.e., immunoglobulin superfamily, cadherins, selectins, integrins, and CD44. 2 These CAMs play a critical role in organ development, inflammation, and cancer invasion and metastasis. [2][3][4][5] Among various cadherin molecules, E-cadherin (E-cad) is the most important in epithelial cells' adhesion. 1,2,4,5 E-cad is a transmembranous glycoprotein of 120 kd localizing in zonula adherens junctions; it mediates by its extracellular domain cell-cell adhesion through calcium dependent, homophylic interactions. 1,2,4,5 The intracellular domain of E-cad is complexed with three submembranous cytosolic proteins, termed ␣-catenin, ␤-catenin, and ␥-catenin. 5 Catenins mediate connection of E-cad to actin filaments 5 and are essential for the functions of E-cad. 6,7 Deletion or mutations of the extra-or intracellular domains of the E-cad gene may result in reduced cell adhesiveness. [8][9][10][11] Cells lacking ␣-catenin are unable to form stable adherens junctions. 6,12 Mutations of ␤-catenin have been reported in a gastric carcinoma cell line, and the resulting truncated ␤-catenin causes loss of E-caddependent cell adhesion. 13 Catenins also play an important role in signal transduction of cells. Catenins bind to the protein of the APC tumor suppressor gene, 14 and ␤-catenin is a common target of signal transduction pathways mediated by proto-oncogene products src, wnt-1, c-erbB2, and epithelial growth factor receptor. [15][16][17] Normal epithelial cells express immunoreactive E-cad and catenins at the cell membrane. 18,19 Reduced or heterogenous expression of E-cad, however, has been reported in a variety of cancers. The down-regulation of E-cad expression has been shown to correlate with high grade and advanced stage in a number of tumors including breast, 18,20,21 esophageal, 18 gastric, 18,22 colorectal, 23 pancreatic, 24 bladder, 25 and prostate 26 carcinomas. To the best of our knowledge, in the human liver only a few studies have described the expression and role of E-cad and catenins in hepatocellular carcinoma (HCC). [27][28][29][30][31][32] However, there have been no comprehensive studies on E-cad and catenins in cholangiocarcinoma (CC).