title: Alterations of E-cadherin, alpha-catenin and beta-catenin expression in neuroendocrine tumors of the gastrointestinal tract.
abstract: Neuroendocrine tumors (NETs) of the gastrointestinal tract comprise a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. These tumors strongly differ from each other on the basis of different pathogenetic, clinical, functional, histological, and prognostic patterns. Previous studies have shown that abnormal and reduced expression of the E-cadherin/catenin complex in several human cancers is associated with tumor dedifferentiation, advanced clinical stages, and poor survival rate. We assessed correlations between the expression of E-cadherin and catenins, Ki-67, and the following clinicopathological factors: age, embryological site of origin, size, histological growth pattern, the depth of penetration into the intestinal wall, and the presence of metastasis. In this study, reduction of membranous E-cadherin expression to a variable degree was detected in more than two-thirds (42 of 51) of gastrointestinal NETs (19 foregut, 8 midgut, and 24 hindgut) belonging to the complete neuroendocrine neoplastic spectrum [18 well-differentiated NETs, 22 well-differentiated neuroendocrine carcinomas (NECs), and 11 poorly differentiated NECs]. The reduction of E-cadherin expression was concomitant with the reduction of alpha-catenin (44 of 51) and beta-catenin (35 of 51) expression. Our immunohistochemical analysis demonstrated significant differences of percentage of membranous positive cells of E-cadherin, alpha-catenin, or beta-catenin between normal tissues and well-differentiated NETs (P=0.0038, P=0.004, and P=0.0329, respectively), well-differentiated NECs (P<0.001, P<0.001, and P<0.001, respectively) and poorly differentiated NECs (P=0.0002, P<0.0002, and P=0.0002, respectively). Among the gastrointestinal NETs, there were significantly more positive cells of E-cadherin, alpha-catenin, or beta-catenin in well-differentiated NETs than well-differentiated NECs (P=0.0006, P=0.0065, and P=0.0001, respectively) or poorly differentiated NECs (P=0.0053, P=0.0041, and P<0.001, respectively). MIB-1 labeling index generally showed a low proliferative activity in well-differentiated NETs (0.49+/-0.37) and well-differentiated NECs (0.662+/-0.66). A high proliferation rate was observed in poorly differentiated NECs (41.518+/-16.59). MIB-1 labeling index was significantly higher in poorly differentiated NECs than well-differentiated NETs and well-differentiated NECs (P<0.0001 and P<0.0001, respectively). E-cadherin, alpha-catenin, and beta-catenin expression were correlated significantly with transmural tumor invasion (P<0.0001, P=0.0001, and P<0.0001, respectively) and with size (P=0.0013, P=0.0001, and P<0.0001, respectively). These results indicate that the alteration in the E-cadherin/catenin expression may be involved in the growth and progression of gastrointestinal NETs.
authors.affiliation: Department of Pathology, University of Tokushima School of Medicine, Japan.
authors.forename: Chiun Chei
authors.initials: CC
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Hirokawa
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Qian
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Horiguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Tashiro
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034961:Antigens, Nuclear; D015820:Cadherins / Q000096:biosynthesis*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin
chemical_list: D034961:Antigens, Nuclear; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin