Colorectal carcinogenesis: Review of human and experimental animal studies

Abstract

This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model) will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma). These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.

Figure 1

Colonic carcinoma, histopathologically diagnosed as moderately differentiated tubular adenocarcinoma (ADC) that developed in a 65-year-old Japanese male. Note an adenoma (AD) and a hyperplastic polyp (HP) surrounding the carcinoma

Figure 2

The histology findings of the colonic mucosa (a and b) and small intestine (c and d). While the villi are lined by a simple columnar epithelium that is continuous with that of the crypts in the small intestine, the colon lacks this structure (villi). The cell types in epithelium of the small intestine include: enterocytes, goblet cells, Paneth's cells, neuroendocrine cells, stem cells and intra-epithelial lymphocytes. The lamina propria extends between the crypts (a, b) and into the core of each villus (b) and contains a rich vascular and lymphatic network into which digestive products are absorbed. The muscularis mucosa lies immediately beneath the base of the crypts

Figure 3

A high-power view of the colonic mucosa (a) and aberrant crypt fission in a familial adenomatous polyposis patient (b). (a) At the ‘A’ zone of the crypt, progenitor proliferating cells and stem cells are present. The ‘B’ zone contains transit-amplifying cells. On the ‘C’ zone of the crypt, there are mature and terminally differentiated cells. In the colonic epithelium, the proliferating crypt precursors and differentiated cells form a contiguous sheet of cells that is in perpetual upward motion. Stem cells reside near the bottom of the crypt and give rise to progenitor cells that are capable of differentiating toward all epithelial lineages. Proliferative progenitor cells arrest their cell cycle and differentiate when they reach near the top of the crypt. In this way, the large number of cells produced by the crypt compartment is compensated by apoptosis at the tip of the crypt in a process that requires about 2–3 days. (b) Aberrant crypt fission in a monocryptal dysplasia

Figure 4

The histopathology findings for the ‘top-down’ (a) and ‘bottom-up’ (b) models. Atypical dysplastic cells are present in the upper (a) and lower (b) parts of the crypts

Figure 5

The histopathology findings of aberrant crypt foci (ACF) from mouse (a and b), rat (c and d) and human (e and f) colon. Methylene blue staining is capable of identifying ACF (a, c and e). These histopathology findings show dyplastic (b and f) and hyperplastic (b) characteristics. (e and f) Familial adenomatous polyposis patient

Figure 6

The histopathology and β-catenin-immunohistochemistry findings of BCAC from mouse (a and b) and human (c and d) colon specimens. BCAC (circled) can be detected on hematoxylin and eosin stain-stained sections (a and c) based on the intensive basophilic nuclei of atypical cells and a few goblet cells in the lesion. β-catenin-immunohistochemistry shows intensive reactivity in the nuclei and/or cytoplasms of atypical cells that form BCAC (b and d)

Figure 7

A MDF (circled) found in the human colon with colorectal cancer. MDF is identified as the lesion with negative staining with high-iron diamine Alcian blue. An ‘insert’ is a high-power view

Figure 8

Various histological types (a–c) of human colonic adenomas with different degrees of dysplasia (d–f) and the histopathology of a hyperplastic polyp (g) and serrated adenoma (h). (a) Tubular adenoma, (b) tubule-villous adenoma, (c) villous adenoma, (d) tubular adenoma with mild-grade dysplasia, (e) tubular adenoma with moderate-grade dysplasia and (f) tubulevillous adenoma with severe-grade dysplasia. (g) The crypts of a hyperplastic polyp are elongated and exhibit cystic dilatation. The epithelium is composed of well-differentiated cells without any atypical features and shows a slightly serrated (saw-tooth) structure. The lesions are macroscopically as small as 0.5 cm in diameter and are always multiple. (h) Serrated adenoma possesses the same serrated architecture of hyperplastic polyps but shows dysplasia of the epithelium. The lesions are larger in size than hyperplastic polyps and are considered pre-malignant in nature, like other adenomas

Figure 9

Histopathology findings of a flat adenoma (a) and a flat adenocarcinoma (b). These lesions are almost flat and are not detected by pre-operative endoscopic examination

Figure 10

The histopathology findings of a dysplasia-associated lesion or mass developed in the colon of a Japanese ulcerative colitis patient. Note that the lesion is composed of many dysplastic glands

Figure 11

The histopathology findings of colonic adenocarcinomas induced by AOM in rats. (a) A polypoid tumor and (b) sessile adenocarcinomas. (c) A mucinous adenocarcinoma, Cancer cells are suspended in mucous lakes

Figure 12

Colonic tumors developed in mice that received AOM and DSS. (a) Macroscopic view shows a number of colonic tumors in the distal colons. (b–e) Histopathology findings of colonic lesions induced by AOM and DSS. Some colonic adenocarcinomas invade the serosa (b). Most adenocarcinomas are of the well-differentiated type, but some moderately differentiated (b) and poorly differentiated types are also observed. Dysplastic crypts (d) are frequently observed in the mucosa, which develop many small adenomas (e)