Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer - PubMed (original) (raw)

Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer

Jordan M Winter et al. Clin Cancer Res. 2008.

Abstract

Purpose: The role of E-cadherin in carcinogenesis is of great interest, but few studies have examined its relevance to pancreatic carcinoma.

Experimental design: We evaluated E-cadherin protein expression by immunohistochemistry in pancreatobiliary cancers having a noncohesive histologic phenotype (21 undifferentiated adenocarcinomas and 7 signet ring carcinomas), comparing the results with pancreatic cancers having a cohesive phenotype (25 moderately differentiated and 14 poorly differentiated adenocarcinomas).

Results: Twenty of 21 undifferentiated cancers had complete absence of E-cadherin expression, as did two signet ring carcinomas. In contrast, cohesive cancers (n = 39) had E-cadherin labeling at the plasma membrane (P < 0.001). Subsets of cancers were also evaluated for beta-catenin expression. All of the cohesive lesions (n = 28) showed a membranous beta-catenin expression pattern, whereas noncohesive foci (n = 7) were characterized by either cytoplasmic labeling or complete absence of beta-catenin protein expression, suggestive of a deficient zonula adherens in noncohesive cancers. E-cadherin promoter hypermethylation was observed in an undifferentiated pancreatic cancer cell line, MiaPaCa-2, whereas two pancreatic cancer cell lines derived from differentiated lesions lacked any evidence of E-cadherin promoter methylation. No pattern of E-cadherin promoter methylation could be determined in three primary cancers having mixed histologic patterns (contained both cohesive and noncohesive foci). No somatic mutations in E-cadherin were identified in noncohesive pancreatic cancers having inactivated E-cadherin.

Conclusions: Noncohesive pancreatic cancers were characterized by the loss of E-cadherin protein expression. Promoter hypermethylation is a possible mechanism of E-cadherin gene silencing in a subset of these cancers.

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Figures

Fig. 1

Fig. 1

Representative histologic appearance (H&E) of a moderately differentiated adenocarcinoma (A) and an anaplastic carcinoma (C). The corresponding E-cadherin immunolabeling studies are provided in B and D, respectively. A normal pancreatic duct with membranous E-cadherin protein expression serves as an internal positive control for the noncohesive cancer (anaplastic carcinoma) shown in D.

Fig. 2

Fig. 2

Representative β-catenin immunolabeling studies of a moderately differentiated adenocarcinoma (A) and an anaplastic carcinoma (B). β-Catenin protein expression in moderately differentiated (C) and anaplastic (D) components of a heterogeneous cancer is also provided.

Fig. 3

Fig. 3

Unmethylated (U)-specific (lanes1, 3, 5, 7, and 9) and methylation (M)-specific (lanes 2, 4, 6, 8, and_10_) PCR amplification of the CpG island in the E-cadherin promoter. Bisulfite-treated water and in vitro – methylated DNA served as negative and positive controls, respectively. A, MiaPaca-2 [undifferentiated (Undiff.) pancreatic cancer], AsPC-1 [differentiated (Diff.) pancreatic cancer], and BxPC-3 (differentiated pancreatic cancer). B, noncohesive (i.e., undifferentiated) and cohesive (i.e., differentiated) foci from three different pancreatic cancers were separated by macrodissecting frozen tumor according to the microscopic appearance of a histologic section from each frozen tumor sample. Neg., negative; Pos., positive.

Fig. 4

Fig. 4

A, Kaplan-Meier survival curves of 9 patients with noncohesive pancreaticobiliary cancers and inactivated E-cadherin (6 anaplastic carcinomas, 1 undifferentiated cancer with osteoclast-like giant cells, and 2 signet ring carcinomas) and 1,229 resected tubuloglandular ductal adenocarcinomas (i.e., cohesive pancreatic cancer; P = 0.002, log-rank test). B, the 1,229 cohesive pancreatic cancers are subgrouped according to histologic grade (well, moderately, and poorly differentiated) and compared with the 9 noncohesive cancers. The P values resulting from comparisons between the nine noncohesive cancers and the subgroups of differentiated pancreatic cancer are P < 0.001, P = 0.0001, and P = 0.03, respectively.

Fig. 5

Fig. 5

Proposed model to explain the different noncohesive histologic phenotypes of pancreaticobiliary cancer based on the timing of E-cadherin inactivation during the pancreatic intraepithelialneoplasia (PanIN) adenocarcinoma sequence. OCGT, osteoclast-like giant cell tumor.

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