Pathology of rodent models of intestinal cancer: progress report and recommendations

Abstract

In October 2010, a pathology review of rodent models of intestinal neoplasia was held at The Jackson Laboratory. This review complemented 2 other concurrent events: a workshop on methods of modeling colon cancer in rodents and a conference on current issues in murine and human colon cancer. We summarize the results of the pathology review and the committee's recommendations for tumor nomenclature. A virtual high-resolution image slide box of these models has been developed. This report discusses significant recent developments in rodent modeling of intestinal neoplasia, including the role of stem cells in cancer and the creation of models of metastatic intestinal cancer.

Figure 1

A) Intramucosal carcinoma in human colorectal adenocarcinomas (arrow) is characterized by infiltration of the lamina propria by tumor cells, without extension into deeper layers of the bowel wall. B) Traditional human serrated adenoma (right), with epithelial infoldings and ectopic crypt formation, compared to tubular normal crypts (left). C) Small adenoma that developed in a mouse following exposure to AOM. It has densely packed neoplastic crypts with low-grade dysplastic changes. D. Invasive adenocarcinoma that developed in a mouse following exposure to AOM, with extension through full thickness of intestinal wall.

Figure 2

A) Mucin-depleted focus characterized by loss of alcian blue-positive goblet cells (alcian blue) and low-grade dysplastic changes. B) Intestinal neoplasms that form in Apc^Pirc/+ rats are often bulky, pedunculated lesions. Although herniation is present in the stalk of the adenoma, focal invasion of muscularis mucosae is also observed (arrow). C) Lrig1^{CreERT2/CreERT2} mice develop intestinal adenomas that are predominantly low grade and overly plaque-like hyperplasia of Brunner’s glands. D) gp130^Y75F mice exposed to AOM and DSS develop pedunculated colonic adenomas. The solid growth pattern in this adenoma indicates high-grade dysplasia.

Figure 3

A) The lesions that develop in Stat3-IKO mice are primary low grade in appearance, but infiltrating irregular crypts, which indicate superficial invasion, were seen in the slides examined by the panel (arrow). B) Colonic adenomas in Apc^Min/+;Smad3^−/− mice arise in a background of colitis and mucosal hyperplasia. This example shows a complex growth pattern that indicates high-grade dysplasia. C) Apc^1638N/wt;Villin-Cre;Tgfbr2^E2flx/E2flx mice develop high-grade adenocarcinomas with prominent intraluminal dirty necrosis, similar to human colorectal adenocarcinomas. D) Lung metastases that form in Villin-Cre;LSL-K-ras^G12D;Tgfbr2^E2flx/E2flx mice are similar to the primary intestinal tumors of these mice.

Figure 4

A) In Apc^flox; LSL-K-ras^G12D mice, adeno-cre administration and mechanical abrasion of colon leads to formation of invasive adenocarcinomas in the distal colon; these are morphologically similar to human colorectal carcinomas. B) Liver metastases that develop in Apc^flox;LSL-K-ras^G12D mice are high-grade carcinomas with a solid and glandular pattern of growth, similar to the primary tumors. C) The K-ras^G12D;Ink4a;Arf^−/− mice develop unusual spindle-cell intestinal tumors; infiltration around non-neoplastic crypts is shown. D) Lung lesions in the slides from K-ras^G12D;Ink4a;Arf^−/− mice were examined by workshop attendees; they contained a papillary adenocarcinoma that differed histologically from the primary tumor.

Figure 5

A) Use of Sleeping Beauty transposon mutagenesis in Apc^+/+ and Apc^Min/+mice resulted in formation of mucinous adenocarcinomas that deeply invaded the intestinal wall. B) Smad3^+/−;Rab25^−/− mice develop rectal adenocarcinomas with mucinous features and deep invasion of intestinal wall and adjacent structures. C) Fabpl^Cre;Apc^flox/+; K-ras^LSL-G12D/+ mice develop adenomas with diffuse high-grade dysplasia and areas of intramucosal adenocarcinoma. D) CDX2P^Cre;Apc^flox/+ mice develop multiple colorectal adenomas. Approximately 17% of mice develop invasive adenocarcinomas, which are shown here, invading the submucosa.