Haigis Kevin M, Hoff Peter D, White Alanna, Shoemaker Alex R, Halberg Richard B, Dove William F
McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9769-73. doi: 10.1073/pnas.0403338101. Epub 2004 Jun 21.
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.
人类遗传性结直肠癌综合征在肿瘤形成方面表现出区域特异性。通过使用携带腺瘤性息肉病 coli 基因（Apc）和/或 DNA 错配修复基因种系突变的小鼠，我们分析了小鼠小肠肿瘤区域性的遗传控制。在携带 Apc 多肠肿瘤突变（Apc(Min)）的杂合 C57BL/6 小鼠中，肿瘤通过体细胞重组导致杂合性缺失而起始，肿瘤优先在小肠远端区域形成。相比之下，在 AKR Apc(Min)遗传背景上通过等位基因沉默起始的肿瘤形成则强烈偏向回盲部。第三种肿瘤区域性表现于 MMR 缺陷的 Apc(Min/+)小鼠中发生的肿瘤，其中 Apc 基因的突变负责肿瘤起始。因此，Apc(Min/+)小鼠小肠中的肿瘤区域性反映了 Apc 野生型等位基因失活的机制。我们重新审视了 Apc(1638N/+)小鼠肿瘤中 Apc 缺失的机制，其中小肠肿瘤以与错配修复缺陷小鼠重叠的区域模式发展。与先前的报道相反，我们发现同基因 C57BL/6 背景下 Apc(1638N/+)小鼠的肿瘤保留了 Apc 的野生型等位基因。我们的研究证明了遗传性肠癌小鼠模型中肿瘤发展的途径特异性区域性，这一观察让人联想到人类结肠中肿瘤发展的区域偏好。也许，可以利用小鼠遗传学和生物学的力量来识别导致肿瘤区域性的遗传和其他因素。
