Animal Models of Stomach Carcinogenesis

Abstract

Although incidences of stomach cancer have decreased over the past several decades, the disease remains an important public health problem. To identify pathological and molecular biochemical mechanisms, various experimental animal models have been established in rats and mice with chemical carcinogens including N -methyl-N -nitro-N -nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU). Helicobacter pylori (H. pylori) is one of the most important factors for human stomach disorders, including neoplasia, and the H. pylori-infected and carcinogen-treated Mongolian gerbil (MG) has proven very useful for analyses of underlying processes. The findings with this model support the hypothesis that intestinal metaplasia is important not as a precancerous lesion but rather as a paracancerous condition and that intestinalization of stomach cancer progresses with chronic inflammation. Furthermore, dose-dependent enhancing effects of salt on stomach carcinogenesis could be demonstrated in MGs treated with MNU and H. pylori modifying surface mucous gel layer. H. pylori itself only causes chronic inflammation and acts as a promoter of stomach carcinogenesis in experimental models. Based on the precise pathological diagnosis of stomach lesions such as noncancerous heterotopic proliferative glands (HPG) and adenocarcinomas, a basis for understanding mechanisms of carcinogenesis has been established on which chemoprevention can be modeled.Keywords. Mouse; rat; Mongolian gerbil; Animal model; Helicobacter pylori; gastric; intestinal metaplasia INTRODUCTION Stomach cancer incidence and mortality have fallen dramatically in the United States and western countries over the past several decades. Nonetheless, it remains a major public health issue as the 4th most common cancer and the 2nd leading cause of cancer death worldwide (Crew and Neugut, 2004). In Japan, stomach cancer remains an important medical problem and its prevention is one of the most important aspects of cancer control strategy, despite its decreasing trend (Tsugane, 2005). Many pathological and biological analyses of stomach carcinomas, including precancerous lesions, have been performed with human samples and experimental animals. In this article, we review the history of stomach carcinoma research from the viewpoint of basic aspects, concentrating especial attention on pathological and biological findings and results for various important modifying factors.

The Transcription Factor MIST1 Is a Novel Human Gastric Chief Cell Marker Whose Expression Is Lost in Metaplasia, Dysplasia, and Carcinoma

“…51 MIST1 staining assesses both lesions (the former via plasma cell staining, the latter indirectly via visualization of metaplastic changes in MIST1-positive chief cells and loss of MIST1-negative parietal cells). The demonstration of spatial heterogeneity in IM also validates animal findings 37,72,99 and expands the concept of gland-to-gland heterogeneity, established in the context of human esophageal dysplasia, 100 into the realm of metaplastic/ paracancerous lesions. Accordingly, CDX2ϩ/MIST1ϩ hybrid nuclei likely represent an initial/intermediate stage of aberrant intestinal-like differentiation.…”

“…52,88,97 As a result, the term paracancerous has been introduced to characterize IM lesions. 10,98,99 The cellular origin of IM in an organ otherwise devoid of intestinal-type cells poses certain experimental problems. 5,12 Nonetheless, animal data support what we present here: strong indications for contributions of the chief cell lineage to the origin of intestinal metaplastic cells.…”

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

“…Cancers of the stomach are the second leading cause of human cancer mortality; however, only a few glandular stomach carcinogens have been identiˆed in experimental animal carcinogenesis (55). Helicobacter pylori (H. pylori) is thought to be one of the most important factors for human stomach disorders, including neoplasia and a new animal model using H. pylori-infected Mongolian gerbils has been proposed (96). Only few organ-speciˆc in vivo short-term test methods for glandular stomach are available including transgenic rodent assay; only results of MNNG (97,98) and MNU (98) were reported and are consistent with our results.…”

Benign reactive lesion with atypical mitosis: New example of an old story

“…One may argue that some of above mentioned chronic pathological processes, for example, long standing ulcerative colitis [4] and gastric intestinal metaplasia [5], are associated with malignant potential. It is true that the role of ulcerative colitis or intestinal metaplasia as pre-neoplastic lesion is well established, associating with various genetic alterations or chromosomal instability [12,13]. It is also true that some of but not all these clinical cases will develop malignant tumors.…”