Morphological and Molecular Processes of Polyp Formation in ApcΔ716 Knockout Mice

摘要: Mutations in the human adenomatous polyposis coli (APC) gene are responsible for not only familial but also many sporadic cancers of digestive tract. Using homologous recombination embryonic stem cells, we recently constructed Apc knockout mice that contained a truncation mutation at codon 716 (Apc(delta716)). The heterozygous developed numerous intestinal polyps. All microadenomas dissected from nascent polyps had already lost wild-type allele, indicating loss heterozygosity (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). We demonstrated cyclooxygenase 2 is induced an early stage and plays key role polyp development Cell 87: 803-809, 1996). have analyzed process these both morphological molecular levels. A small microadenoma initiated as outpocketing pouch single crypt develops into inner (lacteal) side neighboring villus forming double-layer polyp. then enlarges gets folded inside villus. When it fills intravillous space, expands downward extends adjoining villi, rather than rupturing lumen. During this course development, basement membrane remains intact, labeling index cells similar to normal epithelium. As neither transforming growth factor beta1 nor its receptor type II expressed cells. No hot spot mutations K-ras found tissue during stages development. Essentially, same results been obtained colonic well. These suggest adenomas Apc(delta716) very proliferating except lack directed migration along crypt-villus axis.