Frequency of Proliferation, Apoptosis, and Their Ratio During Rat Colon Carcinogenesis and Their Characteristic Pattern in the Dimethylhydrazine-Induced Colon Adenoma and Carcinoma

Abstract

The imbalance between the cell proliferation and cell loss plays a crucial role in the carcinogenesis and tumor progression. However, the direction of these changes is still the matter of discussion. Thus, the aim of this study was to evaluate the proliferative activity, apoptotic activity, and proliferation/apoptosis ratio (P/A) assessed every 6 weeks in the colonic epithelium during 21 weeks of dimethylhydrazine (DMH) treatment in male Wistar rats. Moreover, it is necessary to answer the question whether these analyzed parameters correlate with the grade of differentiation or dysplasia of the induced tumors. It was found that DMH administration enhanced the proliferation in week 12 and 18 when compared with week 6. The proliferation in the control group did not change during the study. Up to week 12 of the experiment, there were no statistically significant differences between proliferative activity in the control and DMH-treated groups. In week 18, the proliferation in DMH-treated group was higher than in the control group. At all time points of the study, the apoptotic activity in the DMH-treated groups was significantly higher than in controls and in both groups, they dropped during the study. In the control group, apoptotic activity decreased in week 18 and was lower in comparison to that in week 6 and 12. In the group treated with DMH, apoptosis dropped at week 12 and was lower than in week 6. The P/A ratio did not change during the study in the control group, but increased in the DMH-treated group. After 21 weeks of DMH administration, 28 cases of colon adenocarcinoma and nine cases of colon adenoma were obtained and classified according to the WHO classification (1989) for human colon tumors. The adenocarcinomas were divided into four groups: well, moderately, poorly differentiated, and signet-ring cell carcinoma. The colon adenomas were divided into three groups: adenoma with mild, moderate, and severe grade of dysplasia. The proliferative activity in signet-ring cell carcinoma was significantly smaller than in well, moderately, and poorly differentiated adenocarcinoma and apoptotic activity was smaller than in well-differentiated adenocarcinoma. A weak (statistically nonsignificant) negative correlation was also observed between the proliferative and apoptotic activity in adenocarcinoma or adenoma and their grade of dedifferentiation or dysplasia, respectively.

Updated Histologic Classification of Adenomas and Carcinomas in the Colon of Carcinogen-treated Sprague-Dawley Rats

“…Several histological classifications of carcinogen-induced colonic adenomas and carcinomas in rats have been proposed (5)(6)(7)(8)(9)(10)(11)(12)(13)). The present study shows that SD rats treated with the colonotropic carcinogen DMH develop supplementary histological neoplastic phenotypes such as traditional (serrated and microtubular) adenomas, GALT-associated adenomas, villous carcinomas, serrated carcinomas, microtubular carcinomas, GALT-associated tubular carcinomas and GALTassociated signet-ring cell carcinomas, in addition to the colonic tumors in rodents reported in the literature (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

“…Several of the histological phenotypes reported here are not included in any of the current classifications of carcinogen-induced colon neoplasias in rodents (5)(6)(7)(8)(9)(10)(11)(12)(13). The purpose of studying colonic carcinogenesis is to explore whether the histological changes found in rodents are similar to those evolving during colorectal carcinogenesis in humans.…”

“…In more recent years, several histological classifications of experimentally-induced colonic adenomas in rats have been proposed (5)(6)(7)(8)(9)(10)(11)(12)(13). Some researchers classify adenomas into tubular, villous and a mixed phenotype and tubulo-villous, others into adenomas with mild, moderate and severe dysplasia, and a third group regard adenomas as only those exhibiting severe dysplasia.…”

“…Some researchers classify adenomas into tubular, villous and a mixed phenotype and tubulo-villous, others into adenomas with mild, moderate and severe dysplasia, and a third group regard adenomas as only those exhibiting severe dysplasia. Similarly, some authors classify invasive carcinomas into well-, moderately and poorly differentiated, and signet-ring cell carcinomas; others into tubular, mucinous, signet-ring cell and undifferentiated; and by a third group into scirrhous, tubular, papillary, tubular-papillary, mucinous, signetring, solid, undifferentiated, and mixed types (5)(6)(7)(8)(9)(10)(11)(12)(13). In contrast, Deschner (14), Maskens (15) and, more recently, Ward and Treuting (16) have asserted that adenocarcinomas often develop de novo, and not from adenomas, therefore, adenomas were not histologically classified.…”

“…Despite the disparate classifications of colonic neoplasias in rodents, the general view has been that colonic carcinomas evolve from conventional (tubular, tubulo-villous or villous) adenomas (5)(6)(7)(8)(9)(10)(11)(12)(13). However, recent studies have disclosed additional histological phenotypes of colonic adenomas and carcinomas in DMH-treated Sprague-Dawley (SD) rats (17)(18)(19) as follows.…”