Analysis of cell cycle-related proteins in gastric intramucosal differentiated-type cancers based on mucin phenotypes: a novel hypothesis of early gastric carcinogenesis based on mucin phenotype

Abstract

Background: Abnormalities of cell cycle regulators are common features in human cancers, and several of these factors are associated with the early development of gastric cancers. However, recent studies have shown that gastric cancer tumorigenesis was characterized by mucin expression. Thus, expression patterns of cell cycle-related proteins were investigated in the early phase of differentiated-type gastric cancers to ascertain any mechanistic relationships with mucin phenotypes.

Methods: Immunostaining for Cyclins D1, A, E, and p21, p27, p53 and beta-catenin was used to examine impairments of the cell cycle in 190 gastric intramucosal differentiated-type cancers. Mucin phenotypes were determined by the expressions of MUC5AC, MUC6, MUC2 and CD10. A Ki-67 positive rate (PR) was also examined.

Results: Overexpressions of p53, cyclin D1 and cyclin A were significantly more frequent in a gastric phenotype than an intestinal phenotype. Cyclin A was overexpressed in a mixed phenotype compared with an intestinal phenotype, while p27 overexpression was more frequent in an intestinal phenotype than in a mixed phenotype. Reduction of p21 was a common feature of the gastric intramucosal differentiated-type cancers examined.

Conclusions: Our results suggest that the levels of some cell cycle regulators appear to be associated with mucin phenotypes of early gastric differentiated-type cancers.

Figure 1

Example of gastric intramucosal differentiated-type cancer. Whereas the index score for cyclin D1 expression is 16 in the gastric cancer mucosa (b), the score is 4 in its surrounding non-neoplastic mucosa (a). The tumor that is shown in figure 1b is regarded as well differentiated adenocarcinoma by Japanese pathologists, although this tumor is considered gastric adenoma or dysplasia by Western pathologists.

Figure 2

Frequencies of cell cycle-related protein expressions in gastric, intestinal and mixed phenotypes. Gastric phenotype cancers are characterized by p53 and cyclin A overexpressions. Although the frequency of p27 overexpression between the intestinal phenotype and other phenotypes did not reach statistical difference, this may be characteristic of the intestinal phenotype. Reduction of p21 and accumulation of β-catenin are commonly observed in the 3 phenotypes. Ki-67 positive rate is higher in the gastric phenotype or mixed phenotype than in the intestinal phenotype. Statistical comparisons used Tamhane tests for all 3 phenotypes.

Figure 3

A representative example of intestinal intramucosal differentiated-type cancer of the gastric phenotype. a. Low power view of tumor tissue. b. High power view of tumor tissue. c. p53 overexpression was seen. d. p21 was reduced. e. p27 was overexpressed. f. Overexpression of cyclin A. g. Low expression of cyclin D1. h. Only Muc2 was expressed in this tumor, suggesting intestinal phenotype.

Figure 4

A new hypothesis for tumorigenesis of gastric intramucosal differentiated-type cancer as defined by the mucin phenotype.