Chemical carcinogenesis of the gastrointestinal tract in rodents: an overview with emphasis on NTP carcinogenesis bioassays

Abstract

Cancers of the stomach and large intestine (LI) are the second and fourth leading causes of human cancer mortality. A review of the National Toxicology Program (NTP) database and the Carcinogenic Potency Database (CPDB) reveals that chemically induced neoplasms of the gastrointestinal tract (GIT) are relatively common. Within the GIT, epithelial tumors of the forestomach in mice and rats and LI of the rat are most common. Generally, there is a high species concordance for forestomach with at least 26 chemicals inducing tumors in both species. Glandular stomach tumors are rare, and the few reported are usually neuroendocrine tumors (carcinoids) originating from the enterochromaffin-like (ECL) cells. Of 290 carcinogenic agents identified by the NTP, 19 (7%) caused intestinal neoplasia, 14 in the rat and 5 in the mouse. Neoplasms occurred in both males and females, exclusively in the small intestine (SI) of the mouse and in the LI or both SI and LI in the rat. Enteric carcinogens (NTP) frequently induced neoplasms at other alimentary sites (oral cavity, esophagus, and stomach). In conclusion, the most common induced GIT tumors are squamous neoplasms of the forestomach, glandular neoplasms of the stomach are rare, and rats appear more prone to developing LI (colorectal) cancer compared to mice.

Figure 1

Squamous cell papilloma (top panel) and squamous cell carcinoma in rats with invasion into submucosa and muscularis (bottom panel). H&E.

Figure 2

Schematic representation outlining the two main proposed pathways of forestomach carcinogenesis in rodents. *Salient features of forestomach tumors induced by genotoxic (MNNG) and non-genotoxic (BHA) chemicals are outlined (Kaneko et al. 2002; Kagawa et al. 1993).

Figure 3

Schematic representation of the “gastrin hypothesis”: a proposed mechanism for induction of gastric carcinoids in rodents by gastric acid blockade. Adapted from Håkanson and Sundler (1990).

Figure 4

Glandular stomach neuroendocrine tumors (carcinoids) observed in the NTP carcinogenicity study with methyleugenol in rats. Malignant neuroendocrine tumor (A, B, C). Three panels on the right (D, E, F) are serial sections of a malignant tumor stained with H&E, Sevier-Munger, and NSE respectively.

Figure 5

Large intestinal adenoma (top panel) and adenocarcinoma (bottom panel) observed in the bromodichloromethane NTP carcinogenicity study in rats. H&E.

Figure 6

Cecal carcinoma observed in the o-nitrotoluene NTP carcinogenicity study in mice (A & B). Tumors were immunohistochemically stained for p53 (C) and beta catenin (D) (Sills, et al., 2004).

Figure 7

Chemical structures of nitrotoluenes and Trihalomethanes (THM) to illustrate that structurally similar chemicals are not site specific carcinogens. o-nitrotoluene, bromodichloromethane, and tribromomethane (left panel) are intestinal carcinogens; whereas p-nitrotoluene, chlorodibromomethane, and chloroform are not intestinal carcinogens.