Gastric cancers are classically categorized into intestinal type and diffuse type based on Lauren's histological classification [1
]. Intestinal-type gastric cancers are characterized by better differentiated, cohesive and glandular-like cell groups. The intestinal type is progressed through multiple steps beginning with atrophic gastritis that is followed by intestinal metaplasia, dysplasia and carcinoma [2
]. Diffuse type corresponds to poorly differentiated, infiltrating and non-cohesive tumor cells. Although diffuse type is not characterized by the multiple proceeding steps, this shows more metastatic phenotype with poorer prognosis.
Several genetic alterations are more frequently observed in either subtype of gastric cancer. Overexpression of ErbB2
is selectively found in intestinal-type tumors and may serve as prognostic marker for tumor invasion [4
expression level was reported to correlate with lymph node or liver metastasis [6
]. Significant decrease in the expression of E-cadherin (CDH1
) has also been described preferentially in diffuse-type gastric cancer ranging from 20% to 90% of frequency [8
]. The decreased expression of CDH1
is caused by LOH or hypermethylation. Interestingly, hereditary diffuse gastric cancer is caused by germline mutations of CDH1
]. In addition, mutation in adenomatous polyposis coli (APC
) which activates Wnt/β-catenin pathway is predominantly found in intestinal-type gastric cancer [13
]. Cyclooxygenase-2 (COX-2
) that is one of the crucial enzymes to synthesize prostaglandin E2
is highly up-regulated in intestinal-type cancers compared with diffuse-type ones [14
]. These genetic alterations could be used as a hallmark of each type of gastric cancer as well as the histological features.
Genome-wide mRNA expression profiles have identified gene signatures to distinguish intestinal- and diffuse-type gastric cancers. Boussioutas et al
] reported that the gene signature distinctive for intestinal type exhibits the up-regulation of proliferation markers related to DNA replication, spindle assembly and chromosome segregation. Down-regulated genes in the signature are associated with epithelial differentiation. Jinawath et al
] also developed another gene signature that is differentially expressed between intestinal-type and diffuse-type cancers with Japanese gastric tumor samples. The intestinal-type signature represented enhancement of cell cycle progression, while the genes associate with extracellular-matrix (ECM) are deregulated in the diffuse type signature. These signatures could provide opportunities of developing biomarkers to diagnose/distinguish the two types in both clinical and preclinical researches.
Transgenic mice that develop gastric tumors present suitable models to decipher gastric tumorigenesis, and identify novel therapeutic targets. We have previously developed several transgenic mice in which prostaglandin E2
production pathway is highly activated specifically in gastric mucosa. K19-C2mE
mice expressing COX-2
and microsomal prostaglandin E synthase-1 (mPGES-1
) develop inflammation-associated hyperplasia [17
]. This was mediated through the recruitment of mucosal macrophages. By crossing the K19-C2mE
mice with K19-Wnt1
mice, cooperative effect of Wnt1 and PGE2
on gastric tumorigenesis was investigated. The K19-Wnt1/C2mE
mice led to the development of dysplastic gastric adenocarcinoma signifying the importance of the Wnt pathway activation to keep the progenitor cells undifferentiated [18
]. To examine the additional effect of the suppression of BMP pathway on the prostaglandin E2
activation, the compound mice of K19-Nog/C2mE
were established. The K19-Nog/C2mE
mice cause the development of gastric hamartomas that are morphologically similar to juvenile polyposis (JP) [19
]. Although the detailed histological and hypothesis-based molecular analysis implicated the pivotal role of prostaglandin E2
, Wnt and Nog pathway respectively in gastric tumorigenesis, it remains elusive whether the K19-C2mE and its compound transgenic mice show similarity to intestinal type or diffuse type of human gastric cancers when analyzed by non-biased global expression profile.
In order to identify which types of human gastric tumors (intestinal or diffuse type) the C2mE-related mice are more similar to, we compared expression profile of the two types of human gastric cancer with those of K19-C2mE, K19-Wnt1/C2mE, and K19-Nog/C2mE transgenic mice.