Pathogenesis of rat colon carcinomas induced by N-methyl-N-nitrosourea

Colon specimens were obtained from 45 young male and female inbred CDF rats between 11 and 42 weeks after they began to receive intrarectal injections of the carcinogen N-methyl-N-nitrosourea (MNU) 43--108 mg, total dose); specimens were also obtained from 26 control rats. Well-developed tumors from rats receiving MNU generally presented grossly as polyps; histologically, as invasive adenocarcinomas that had not metastasized. These tumors resembled their human counterparts. Focal epithelial atypias were found in grossly normal mucosa both from rats that had not yet developed tumors and from tumor-bearing rats. Such foci typically consisted of low columnar cells with enlarged nuclei, increased number of mitoses, cytoplasmic basophilia, and reduced cytoplasmic mucus. Serial section studies of minute foci of atypia indicated that some of them arose from normal deep crypt cells. Transitions were frequently found between atypical foci and in situ or invasive carcinomas. Less commonly, adenomatous epithelium was identified in the early lesions or within the frank adenocarcinomas. It was concluded that most invasive carcinomas in this rat model originate in foci of epithelial atypia, which are found with increasing frequency in the flat mucosa during treatment with MNU, but that some carcinomas also arise from adenomatous epithelium.