Objective The glands of the stomach body and antral mucosa contain a complex compendium of cell lineages. In lower mammals, the distribution of oxyntic glands and antral glands define the anatomical regions within the stomach. We examined in detail the distribution of the full range of cell lineages within the human stomach. Design We determined the distribution of gastric gland cell lineages with specific immunocytochemical markers in entire stomach specimens from three non-obese organ donors. Results The anatomical body and antrum of the human stomach were defined by the presence of ghrelin and gastrin cells, respectively. Concentrations of somatostatin cells were observed in the proximal stomach. Parietal cells were seen in all glands of the body of stomach as well as in over 50% of antral glands. MIST1-expressing chief cells were predominantly observed in the body, although individual glands of the antrum also showed MIST1-expressing chief cells. While classically-described antral glands were observed with gastrin cells and deep antral mucous cells without any parietal cells, we also observed a substantial population of mixed-type glands containing both parietal cells and G cells throughout the antrum. Conclusions Enteroendocrine cells show distinct patterns of localization in the human stomach. The existence of antral glands with mixed cell lineages indicates that human antral glands may be functionally chimeric with glands assembled from multiple distinct stem cell populations.

Upper gastrointestinal neoplasia in the esophagus, stomach and pancreas is associated with the formation of pre-neoplastic metaplasias. We have previously reported the up-regulation of Human epididymis protein 4 (HE4) in all metaplasias in the stomach of humans and mice. We have now sought to evaluate the expression of HE4 in metaplasias/pre-neoplastic precursors and cancers of the human stomach, pancreas and esophagus. Tissue microarrays for gastric cancers, pancreatic cancers and esophageal adenocarcinoma were stained with antibodies against HE4. Immunostaining was quantified by digital imaging and the results were evaluated to assess expression in metaplasias, expression in cancer pathological subtypes and the effects of expression on survival in cancer patients. In gastric cancer patients from Korea, HE4 was detected in 74% of intestinal and 90% of diffuse cancers, while in a gastric cancer cohort from Johns Hopkins HE4 was detected 74% of intestinal type and 92% of diffuse cancers. Nevertheless, in both cohorts there was no impact of HE4 expression on overall survival. In the esophagus, we observed expression of HE4 in scattered endocrine cells within Barrett’s esophagus samples, but Barrett’s columnar metaplasias and HE4 was detected in only 2% of esophageal adenocarcinomas. Finally, in the pancreas, HE4 expression was not observed in pancreatic intraepithelial neoplasia (PanIN) lesions, but 46.8% of pancreatic adenocarcinomas expressed HE4 expression. Still, we did not observe any influence of HE4 expression on survival. The results suggest that HE4 is up-regulated during gastric and pancreatic carcinogenesis.

Expression of the α2β1 integrin, a receptor for collagens and laminin, is altered during tumor progression. Recent studies have linked polymorphisms in the α2 integrin gene with oral, squamous cell carcinoma (SCC). To determine the α2β1 integrin's role in SCC progression, we crossed α2-null mice with K14-HPV16 transgenic animals. Pathological progression to invasive carcinoma was evaluated in HPV-positive, α2-null (HPV/KO) and HPV-positive, wild-type (HPV/WT) animals. α2β1 integrin expression stimulated progression from hyperplasia and papillomatosis to dysplasia with concomitant dermal mast cell infiltration. Moreover, lymph node metastasis was decreased by 31.3% in HPV/KO, compared to HPV/WT, animals. To evaluate the integrin-specific impact on the malignant epithelium versus the microenvironment, we developed primary tumor cell lines. Although transition from dysplasia to carcinoma was unaltered during spontaneous tumor development, isolated primary HPV/KO SCC cell lines demonstrated decreased migration and invasion, compared to HPV/WT cells. When HPV/WT and HPV/KO SCC cells were orthotopically injected into WT or KO hosts, tumor α2β1 integrin expression resulted in decreased tumor latency, regardless of host integrin status. HPV/WT SCC lines failed to demonstrate a proliferative advantage in vitro, however, the HPV/WT tumors demonstrated increased growth compared to HPV/KO SCC lines in vivo. Although contributions of the integrin to the microenvironment cannot be excluded, our studies indicate that α2β1 integrin expression by HPV-transformed keratinocytes modulates SCC growth and progression.

The complex interplay between tumor cells and their surrounding microenvironment define cancer progression. The α2β1 integrin, expressed by subsets of epithelial, endothelial, fibroblast, and inflammatory cells, is a receptor for matrix and non-matrix ligands, including collagens, laminins, and immunomodulatory molecules C1q and collectins. Altered α2β1 integrin expression in cancer has been linked to tumor progression; recent studies have linked polymorphisms in the α2β1 integrin with oral, squamous cell carcinoma (SCC). We hypothesized that the α2β1 integrin functions in SCC initiation or progression by modulating interactions between the squamous epithelium and/or tumor microenvironment. To determine the role of α2β1 integrin expression on SCC progression, we crossed α2β1 integrin-null mice with K14-HPV transgenic animals, a well-established model of epithelial carcinogenesis. Progression from hyperplasia to dysplasia and invasive carcinoma was evaluated in HPV-positive, α2β1 integrin-null (HPV/KO) and HPV-positive, wild-type (HPV/WT) animals. Our data demonstrate that during SCC progression, expression of the α2β1 integrin stimulates progression from hyperplasia and papillomatosis to dysplasia. Decreased dysplasia in HPV/KO animals at early time points of tumor progression directly correlated with reduced dermal mast cell infiltration. Moreover, lymph node metastasis was decreased by 31.3% and associated with alterations in lymphatic vasculature within the tumor microenvironment of HPV/KO, compared to HPV/WT, animals. Since these studies utilized global α2β1 integrin knockout mice, we developed primary tumor cell lines to evaluate the integrin-specific impacts on the malignant epithelium versus the host microenvironment. Although transition from dysplasia to carcinoma was unaltered in our original tumor studies, isolated primary HPV/KO SCC cell lines had decreased invasion in a 3D transwell migration assay, compared to HPV/WT cells. When HPV/WT and HPV/KO SCC cell lines were orthotopically injected into either WT or KO hosts, α2β1 integrin-specific expression on tumor cells decreased tumor latency, regardless of host integrin status. HPV/WT SCC lines failed to demonstrate a proliferative advantage in vitro, however, the HPV/WT tumors demonstrated increased growth rates compared to HPV/KO SCC lines in vivo. Therefore, these latter data suggest that contributions of the tumor microenvironment cannot be excluded and are likely modulating SCC growth characteristics. Our studies indicate the α2β1 integrin plays diverse roles during tumor progression, acting on the tumor and tumor microenvironment. Although the α2β1 integrin plays no obvious role during normal development, exposure to physiological stresses, such as cancer, unmasks functions of the α2β1 integrin to reveal its importance in tissue biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 415. doi:10.1158/1538-7445.AM2011-415

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