Shoemaker A R, Moser A R, Midgley C A, Clipson L, Newton M A, Dove W F
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10826-31. doi: 10.1073/pnas.95.18.10826.
Previous studies of Min/+ (multiple intestinal neoplasia) mice on a sensitive genetic background, C57BL/6 (B6), showed that adenomas have lost heterozygosity for the germ-line ApcMin mutation in the Apc (adenomatous polyposis coli) gene. We now report that on a strongly resistant genetic background, AKR/J (AKR), Min-induced adenoma multiplicity is reduced by about two orders of magnitude compared with that observed on the B6 background. Somatic treatment with a strong mutagen increases tumor number in AKR Min/+ mice in an age-dependent manner, similar to results previously reported for B6 Min/+ mice. Immunohistochemical analyses indicate that Apc expression is suppressed in all intestinal tumors from both untreated and treated AKR Min/+ mice. However, the mechanism of Apc inactivation in AKR Min/+ mice often differs from that observed for B6 Min/+ mice. Although loss of heterozygosity is observed in some tumors, a significant percentage of tumors showed neither loss of heterozygosity nor Apc truncation mutations. These results extend our understanding of the effects of genetic background on Min-induced tumorigenesis in several ways. First, the AKR strain carries modifiers of Min in addition to Mom1. This combination of AKR modifiers can almost completely suppress spontaneous intestinal tumorigenesis associated with the Min mutation. Second, even on such a highly resistant genetic background, tumor formation continues to involve an absence of Apc function. The means by which Apc function is inactivated is affected by genetic background. Possible scenarios are discussed.
先前在敏感遗传背景C57BL/6（B6）的Min/+（多重肠道肿瘤）小鼠上开展的研究表明，腺瘤在腺瘤性息肉病大肠杆菌（Apc）基因中已失去种系ApcMin突变的杂合性。我们现在报告，在强抗性遗传背景AKR/J（AKR）下，与在B6背景上观察到的情况相比，Min诱导的腺瘤多发性降低了约两个数量级。用强诱变剂进行体细胞处理会以年龄依赖性方式增加AKR Min/+小鼠的肿瘤数量，这与先前报道的B6 Min/+小鼠的结果相似。免疫组织化学分析表明，未处理和处理过的AKR Min/+小鼠的所有肠道肿瘤中Apc表达均受到抑制。然而，AKR Min/+小鼠中Apc失活的机制通常与B6 Min/+小鼠中观察到的不同。尽管在一些肿瘤中观察到杂合性缺失，但相当比例的肿瘤既未显示杂合性缺失也未显示Apc截短突变。这些结果从几个方面扩展了我们对遗传背景对Min诱导的肿瘤发生影响的理解。首先除了Mom1之外，AKR品系还携带Min的修饰基因。AKR修饰基因的这种组合几乎可以完全抑制与Min突变相关的自发性肠道肿瘤发生。其次，即使在如此高度抗性的遗传背景下，肿瘤形成仍然涉及Apc功能的缺失。Apc功能失活的方式受遗传背景影响。文中讨论了可能的情况。
