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Long-lived Min Mice Develop Advanced Intestinal Cancers through a Genetically Conservative Pathway

¹ McArdle Laboratory for Cancer Research, ² Research Animal Resources Center Comparative Pathology Laboratory, ³ Paul P. Carbone Comprehensive Cancer Center, and ⁴ Laboratory of Genetics, University of Wisconsin; ⁵ Genetics Analysis Group, Promega Corporation, Madison, Wisconsin; ⁶ Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee; and ⁷ Cancer Research Institute, University of California, San Francisco, California

Requests for reprints: William F. Dove, University of Wisconsin, 1400 University Avenue, Madison, WI 53706. Phone: 608-262-4977; Fax: 608-262-2824; E-mail: dove{at}oncology.wisc.edu.

Key Words: intestinal neoplasia • invasive adenocarcinomas • local metastasis • microsatellite instability • chromosomal instability

C57BL/6J mice carrying the Min allele of Adenomatous polyposis coli (Apc) develop numerous adenomas along the entire length of the intestine and consequently die at an early age. This short lifespan would prevent the accumulation of somatic genetic mutations or epigenetic alterations necessary for tumor progression. To overcome this limitation, we generated F₁ Apc^Min/+ hybrids by crossing C57BR/cdcJ and SWR/J females to C57BL/6J Apc^Min/+ males. These hybrids developed few intestinal tumors and often lived longer than 1 year. Many of the tumors (24-87%) were invasive adenocarcinomas, in which neoplastic tissue penetrated through the muscle wall into the mesentery. In a few cases (3%), lesions metastasized by extension to regional lymph nodes. The development of these familial cancers does not require chromosomal gains or losses, a high level of microsatellite instability, or the presence of Helicobacter. To test whether genetic instability might accelerate tumor progression, we generated Apc^Min/+ mice homozygous for the hypomorphic allele of the Nijmegen breakage syndrome gene (Nbs1^B) and also treated Apc^Min/+ mice with a strong somatic mutagen. These imposed genetic instabilities did not reduce the time required for cancers to form nor increase the percentage of cancers nor drive progression to the point of distant metastasis. In summary, we have found that the Apc^Min/+ mouse model for familial intestinal cancer can develop frequent invasive cancers in the absence of overt genomic instability. Possible factors that promote invasion include age-dependent epigenetic changes, conservative somatic recombination, or direct effects of alleles in the F₁ hybrid genetic background. [Cancer Res 2009;69(14):5768–75]

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