Ken'ichi Inada

All of the different types of stomach epithelial cells are known to be derived from a single progenitor cell in each gland. Similarly, cancers develop from single cells, based on data from clonality analysis in C3H/HeN<---->BALB/c chimeric mice. Using gastric and intestinal epithelial cell markers, intestinal metaplasia (IM) can be divided into two major types: a gastric and intestinal (GI) mixed type, and a solely intestinal (1) type. Ectopic expression of Cdx genes and down-regulation of Sox2 in isolated single GI mixed IM glands suggests abnormal differentiation of stem cells that can produce both gastric (G) and I type cells. Similarly, phenotypic expression of gastric cancer cells of each histological type can be clearly classified into G and I type epithelial cells. The heterogeneity of phenotypic expression of gastric cancer cells in individual cancers is assumed to reflect this intrinsic potential for differentiation in two directions. Gastric cancers at early stages, independent of the histological type, mainly consist of G type cells, and phenotypic shift from G to I type expression is clearly observed with progression. The data thus suggest IM may not be a preneo-plastic change in gastric carcinoma, but rather that cells of the I type may appear independently in the gastric mucosa in IM and in gastric cancers. Intestinalization of gastric mucosa and cancer cells may represent a kind of homeotic transformation. Whether disturbance of the regulation of Sox2 and Cdx genes may be of importance to the biological behavior of gastric cancers should therefore be clarified in future studies. (Cancer Sci 2003; 94: 135141).

Gastrointestinal stromal tumors (GISTS) are the most common mesenchymal tumors. The molecular etiology is the result of mutations in the c-Kit gene. The mutant c-Kit proteins, which are activated without a stem cell factor, contribute to the tumor development. STI571 selectively inhibits c-Kit, BCR-ABL, and PDGFR tyrosine kinases. Based on this potential to inhibit critical c-Kit function in GISTS, case studies have reported effective outcomes following treatment with STI571. This case report describes a highly effective use of STI571 in a 54-year-old woman with multiple liver metastases from a GIST originating in the duodenum.

Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2 : inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia.

Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M.<br /> Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2 : inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia.

Sugiyama Y, Kato T, Nakazato H, Ito K, Mizuno I, Kanemitsu T, Matsumoto K, Yamaguchi A, Nakai K, Inada K, Tatematsu M. Retrospective study on thymidylate synthase as a predictor of outcome and sensitivity to adjuvant chemotherapy in patients with curatively resected colorectal cancer.

Histological features and genetic changes induced by X-rays in intestinal metaplasia (IM) in rats were assessed by histochemistry and immunohistochemistry. A time course study and a PCR-SSCP analysis were performed. The IMs in rats were classified into two major types according to the cells forming the metaplastic glands. The first (the GI type) had both gastric and intestinal type cells forming the metaplastic glands. The second (the I-sol type) had solely intestinal cells forming the metaplastic glands. This characterization is similar to that used to define human IMs. The occurrence of IMs of the I-sol and GI types in rats gradually increased with time after X-ray irradiation. The number of IMs of the GI type was relatively high at 2 and 4 weeks after X-ray irradiation, and was low thereafter. On the other hand, the number of IMs of the I-sol type was extremely low at 2 weeks after treatment, then increased with time, and reached a maximum at 77 weeks after treatment. In the PCR-SSCP analysis, there were no alterations of the H-ras, Kras, and p53 genes in the IM glands of rats treated with X-ray irradiation 8 weeks earlier. These observations suggest that the phenotypic change from IMs of the GI type to the I-sol type occurred without ras and p53 gene alterations.

Sugiyama Y, Kato T, Nakazato H, Ito K, Mizuno I, Kanemitsu T, Matsumoto K, Yamaguchi A, Nakai K, Inada K, Tatematsu M.<br /> Retrospective study on thymidylate synthase as a predictor of outcome and sensitivity to adjuvant chemotherapy in patients with curatively resected colorectal cancer.

Histological features and genetic changes induced by X-rays in intestinal metaplasia (IM) in rats were assessed by histochemistry and immunohistochemistry. A time course study and a PCR-SSCP analysis were performed. The IMs in rats were classified into two major types according to the cells forming the metaplastic glands. The first (the GI type) had both gastric and intestinal type cells forming the metaplastic glands. The second (the I-sol type) had solely intestinal cells forming the metaplastic glands. This characterization is similar to that used to define human IMs. The occurrence of IMs of the I-sol and GI types in rats gradually increased with time after X-ray irradiation. The number of IMs of the GI type was relatively high at 2 and 4 weeks after X-ray irradiation, and was low thereafter. On the other hand, the number of IMs of the I-sol type was extremely low at 2 weeks after treatment, then increased with time, and reached a maximum at 77 weeks after treatment. In the PCR-SSCP analysis, there were no alterations of the H-ras, Kras, and p53 genes in the IM glands of rats treated with X-ray irradiation 8 weeks earlier. These observations suggest that the phenotypic change from IMs of the GI type to the I-sol type occurred without ras and p53 gene alterations.

Expression of cathepsin E in epithelial cells of the normal glandular stomach and small intestine, intestinal metaplasia, stomach and small intestinal tumors, was investigated in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Immunohistochemically, parietal cells were found to be moderately positive while surface mucous and pyloric gland cells demonstrated marked staining. Intestinal metaplastic glands in the stomach and normal small intestinal epithelial cells did not have any cathepsin E reactivity although some regenerative small intestinal epithelium proved positive. Histochemical staining for mucin demonstrated all stomach tumors (adenomatous hyperplasias and well-differentiated adenocarcinomas) to be mainly comprised of gastric epithelial type cells (pyloric gland and surface mucous cells), with intestinal epithelial type cells (goblet and intestinal absorptive cells) being only occasional findings. Almost all of the gastric epithelial type cells showed cathepsin E reactivity in their cytoplasm while the intestinal epithelial cell type cells were mainly consisted of cathepsin E negative one like those in small intestinal cancers. Catepsin E may thus be a useful marker for cell differentiation of stomach tumors and their intestinalization. Cancers arising in the small intestine consisted of intestinal epithelial cell type cells, but no stomach tumors consisted predominantly of this type, so that there was no suggestion of any derivation from intestinal metaplasias in rats.

Expression of cathepsin E in epithelial cells of the normal glandular stomach and small intestine, intestinal metaplasia, stomach and small intestinal tumors, was investigated in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Immunohistochemically, parietal cells were found to be moderately positive while surface mucous and pyloric gland cells demonstrated marked staining. Intestinal metaplastic glands in the stomach and normal small intestinal epithelial cells did not have any cathepsin E reactivity although some regenerative small intestinal epithelium proved positive. Histochemical staining for mucin demonstrated all stomach tumors (adenomatous hyperplasias and well-differentiated adenocarcinomas) to be mainly comprised of gastric epithelial type cells (pyloric gland and surface mucous cells), with intestinal epithelial type cells (goblet and intestinal absorptive cells) being only occasional findings. Almost all of the gastric epithelial type cells showed cathepsin E reactivity in their cytoplasm while the intestinal epithelial cell type cells were mainly consisted of cathepsin E negative one like those in small intestinal cancers. Catepsin E may thus be a useful marker for cell differentiation of stomach tumors and their intestinalization. Cancers arising in the small intestine consisted of intestinal epithelial cell type cells, but no stomach tumors consisted predominantly of this type, so that there was no suggestion of any derivation from intestinal metaplasias in rats.