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

Abstract：

: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 (Apc(Min)), 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 Apc(Min) genetic background is strongly skewed toward the ileocecal junction. A third tumor regionality is displayed by tumors that develop in MMR-deficient Apc(Min/+) mice, in which mutation of the Apc gene is responsible for tumor initiation. Thus, tumor regionality in the small intestine of Apc(Min/+) reflects the mechanism by which the wild-type allele of Apc is inactivated. We have reexamined the mechanism of Apc loss in tumors from Apc(1638N/+) 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 Apc(1638N/+) 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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Haigis KM,Hoff PD,White A,Shoemaker AR,Halberg RB,Dove WF

doi

10.1073/pnas.0403338101

keywords:

subject

Has Abstract

pub_date

2004-06-29 00:00:00

pages

9769-73

issue

eissn

0027-8424

issn

1091-6490

pii

0403338101

journal_volume

101

pub_type

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