Developmental abnormalities in multiple proliferative tissues of Apc^Min/+ mice

Abstract

Germ-line mutation of the Apc gene has been linked to familial adenomatous polyposis (FAP) that predisposes to colon cancer. Apc(Min/+) mice, heterozygous for the Apc gene mutation, progressively develop small intestinal tumours in a manner that is analogous to that observed in the colon of patients with FAP (Su et al. 1992; Fodde et al. 1994; Moser et al. 1995). We have studied the effects of Apc gene mutation on murine intestinal and extra-intestinal, proliferatively active tissues. We have contrasted the histology to that of the age- and sex-matched wild-type C57BL/6 mice. Histological assessment of the normal appearing intestinal mucosa demonstrates minimal change in size of crypts. In contrast, villi are longer in the ileum of Apc(Min/+) mice relative to C57BL/6 mice at 12 and 15 weeks of age. Vigorous splenic haematopoiesis in Apc(Min/+) mice was seen at 12 and 15 weeks of age, as reflected by marked splenomegaly, increased splenic haematopoietic cells and megakaryocytes. Peripheral blood counts, however, did not differ between C57BL/6 and Apc(Min/+) mice at 15 weeks of age. Lymphoid depletion in Apc(Min/+) mice was characterized by diminished numbers of splenic lymphoid follicles and small intestinal Peyer's patches. The ovaries of 12- and 15-week-old Apc(Min/+) mice exhibited increased numbers of atretic follicles, and estrous cycling by serial vaginal smears showed tendency of elongation in the mutant mice during these age ranges. The testicles of 10-week-old Apc(Min/+) mice showed increased numbers of underdeveloped seminiferous tubules. Collectively, these data suggest that, in addition to its obvious effects upon intestinal adenoma formation, Apc gene mutation causes impairment of developmental and apparent differentiation blockade in proliferative tissues, including those of the haematopoietic system, lymphoid and reproductive tract.

Adenomatous Polyposis Coli (APC) Is Essential for Maintaining the Integrity of the Seminiferous Epithelium

“…Although deletion and duplication of the APC has been associated with testicular dysgenesis syndrome (TDS) and other testicular abnormities (48), its loss in SCO has heretofore not been described. Additionally, mutations and hypermethylation of the APC gene has been observed in human testicular yolk sac tumor patients (2), and a progressive decrease in male fertility was noted in APC min/ϩ mice, a well-studied mouse model of colon cancer (49). However, the mechanisms involved in APC-mediated infertility were not reported.…”

Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice

“…We first tested whether chronically administered zebularine could prevent or delay tumor progression in Apc Min/+ (Min) mice. Min mice have a nonsense mutation in the adenomatous polyposis coli (Apc) gene, which leads to the development of multiple adenomas in the intestines along with other phenotypes such as anemia, splenomegaly, and impaired development of proliferative tissues (19)(20)(21). We found that oral administration of zebularine resulted in decreased tumorigenicity.…”

“…and treated males at the time of euthanasia (21). However, a significant decrease in the weight and size of spleen was noted in the treated female group (P = 0.0004; Supplementary Fig.…”

Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis

“…Min/+ mice undergo thymic atrophy and splenomegaly with lymphodepletion as well as loss of Peyer's patches accompanying intestinal tumorigenesis (17,18). It has also been reported that the rapid onset of tumors in the intestine coincides with the loss of thymus (15).…”