Three Pathways of Colonic Carcinogenesis in Rats

Colorectal cancer (CRC) is one of the more intensively studied human malignancies. For many years, the general view has been that the vast majority of CRCs in humans evolve from conventional (tubular or villous) adenomas via the adenoma-carcinoma pathway. More recently, serrated colorectal polyps (hyperplastic polyps, sessile serrated polyps and traditional serrated adenomas) have emerged as an alternative pathway of colorectal carcinogenesis in humans. Archival sections from early experiments in Sprague-Dawley (SD) rats injected with dimethylhydrazine (DMH) were reviewed and the histology of colonic neoplasias was re-evaluated. Out of 215 colonic neoplasias, 9% were serrated adenomas and 6% serrated carcinomas, 11% conventional adenomas, 39% highly differentiated carcinomas, 21% gut-associated lymphoid tissue (GALT) carcinomas, 13% signet-ring cell carcinomas, and 1% villous carcinomas. In a more recent review of archived sections from DMH-treated rats with colonic GALT follicles, dysplastic crypts exhibiting asymmetrical bifurcations in GALT mucosa were found in 49% and colonic GALT carcinomas in 53% of 276 DMH-treated rats. Histology of the 146 colonic GALT-carcinomas revealed highly differentiated carcinoma in 75%, signet-ring cell carcinoma in 20%, mucinous carcinomas in 3% and mixed in the remaining 2%. Highly differentiated carcinomas were seen to evolve from dysplastic crypts with asymmetric bifurcations and from adenomas and signet-ring cell carcinomas, and from non-dysplastic crypts having goblet cells with marked anisocytosis. It is apparent that DMH treatment in SD rats induced conventional adenomas, conventional carcinomas, serrated adenomas, serrated carcinomas and GALT carcinomas. The paradigm permits to monitor in detail the early histological steps that epitomize the three alternative pathways of colonic carcinogenesis in SD rats. This model might be useful for analyzing different molecular aberrations evolving during the conventional adenoma-carcinoma pathway, the serrated carcinoma pathway, and the GALT carcinoma pathway of colonic carcinogenesis, under standard laboratory conditions.