Tumor regionality in the mouse intestine reflects the mechanism of loss of Apc function

AUTOR(ES)

Haigis, Kevin M.

FONTE

National Academy of Sciences

RESUMO

Inherited colorectal cancer syndromes in humans exhibit regional specificity for tumor formation. By using mice with germline mutations in the adenomatous polyposis coli gene (Apc) and/or DNA mismatch repair genes, we have analyzed the genetic control of tumor regionality in the mouse small intestine. In C57BL/6 mice heterozygous for the Apc multiple intestinal neoplasia mutation (ApcMin), in which tumors are initiated by loss of heterozygosity by means of somatic recombination, tumors form preferentially in the distal region of the small intestine. By contrast, the formation of tumors initiated by allelic silencing on the AKR ApcMin genetic background is strongly skewed toward the ileocecal junction. A third tumor regionality is displayed by tumors that develop in MMR-deficient ApcMin/+ mice, in which mutation of the Apc gene is responsible for tumor initiation. Thus, tumor regionality in the small intestine of ApcMin/+ reflects the mechanism by which the wild-type allele of Apc is inactivated. We have reexamined the mechanism of Apc loss in tumors from Apc1638N/+ mice, in which tumors of the small intestine develop in a regional pattern overlapping that of mismatch repair-deficient mice. In contrast to previous reports, we find that tumors from Apc1638N/+ mice on a congenic C57BL/6 background maintain the wild-type allele of Apc. Our studies demonstrate a pathway-specific regionality for tumor development in mouse models for inherited intestinal cancer, an observation that is reminiscent of the regional preference for tumor development in the human colon. Perhaps, the power of mouse genetics and biology can be harnessed to identify genetic and other factors that contribute to tumor regionality.

Documentos Relacionados

• Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant loss of Apc+ from all tumor lineages
• Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene
• Loss-of-function genetics in mammalian cells: the p53 tumor suppressor model
• Mechanism for elimination of a tumor suppressor: Aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma
• The APC gene product in normal and tumor cells.