Summary. We have previously suggested that an origin of a stomach cancer is from a progenitor cell specializing toward exocrine cell (Exo-cell) lineages. To clarify whether our hypothesis is correct or not, we analyzed the expression of Exo-cell and endocrine cell (End-cell) markers in a series of lesions for comparison. We evaluated chromogranin A (CgA) expression in 37 early and 73 advanced stomach cancers, in 30 stomach adenomas, in 8 carcinoid tumors, and in 4 endocrine cell carcinomas (ECCs) with assessment of gastric and/or intestinal (G/I) phenotypes in both Exo-cell and End-cell by immunohistochemistry. CgA expression was observed in 10.8% of the early and 16.4% of the advanced stomach cancers, respectively. The End-cell G/I phenotypes were in line with the Exo-cell counterparts in the CgA-positive stomach cancerous areas, and there was strong association between Cdx2 expression and the intestinal End-cell markers. All of the adenoma cases had the intestinal Exo-cell phenotypic expression, with the positive link between Exo-cell and End-cell G/I phenotypes. All stomach carcinoids had CgA expression but no expression of Exo-cell markers. In conclusion, most stomach cancers might develop from a progenitor cell specializing towards Exo-cell lineages, but some cases possessed both Exo-cell and End-cell markers with maturely differentiated phenotypes. In such cases, Exo-cell and End-cell phenotypes were found to correlate strongly, suggesting the possibility of histogenesis from “cancer stem cells”. Key words: Stomach cancers, Endocrine cell, Phenotypes, Progenitor cell, Cancer stem cells Introduction Gastrointestinal stem cells have the capacity for long-term self-replication and the ability to give rise to all other epithelial cell lineages (Schier and Wright, 2005). We have previously shown that each epithelial gland in the alimentary tract is derived from a single stem cell, based on clonality analysis using a strain specific antibody in C3H/HeN⇔BALB/c chimeric mice (Tatematsu et al., 1994, 1996; Tsukamoto et al., in press). The stem cell gives rise to two kinds of progenitor cell directly: (i) progenitor cell specializing toward exocrine cell (Exo-cell) lineages; and (ii) progenitor cells specializing toward endocrine cell (End- cell) lineages (Tatematsu et al., 2003, 2005). Regarding the histogenesis of stomach cancer, if the cancer originated from the stem cell, the mixture of differentiation toward both Exo-cell and End-cell lineages should be observed more frequently and homogenously in the whole stomach cancerous tissues, although in fact it is observed rarely. Stomach epithelial tumors are divided into two major types: Exo-cell type (adenomas and carcinomas) and End-cell type [carcinoid tumors and endocrine cell carcinomas (ECC)]. Therefore, we have suggested the hypothesis that the origin of stomach cancers is from a progenitor cell specializing towards an Exo-cell lineage (Tatematsu et al., 2005). However, there have been several reports that chromogranin A (CgA), an End-cell differentiation marker, was immunohistochemically found in about 15- 70% of human stomach cancers, although with Gastric and intestinal phenotypic correlation between exocrine and endocrine components in human stomach tumors Y. Takenaka 1,2,* , T. Tsukamoto 1,* , T. Mizoshita 1 , N. Ogasawara 1 , N. Hirano 1 , T. Otsuka 1 , H. Ban 1 , T. Nakamura 3 , Y. Yamamura 4 , M. Kaminishi 2 and M Tatematsu 1 1 Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan, 2 Department of Gastrointestinal Surgery, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan, 3 Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan and 4 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Japan *These authors contributed equally to this work. Histol Histopathol (2007) 22: 273-284 Offprint requests to: Tetsuya Tsukamoto, MD, Ph D, Division of Oncological Pathology, Aichi Cancer Centr Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. e-mail: ttsukamt@aichi-cc.jp http://www.hh.um.es Histology and Histopathology Cellular and Molecular Biology