Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Long-lived Min mice develop advanced intestinal cancers through a genetically conservative pathway. Cancer Res 2009 Jul 15;69(14):5768-75

Date

07/09/2009

Pubmed ID

19584276

Pubmed Central ID

PMC2775466

DOI

10.1158/0008-5472.CAN-09-0446

Abstract

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 F(1) 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(DeltaB)) 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 F(1) hybrid genetic background.

Author List

Halberg RB, Waggoner J, Rasmussen K, White A, Clipson L, Prunuske AJ, Bacher JW, Sullivan R, Washington MK, Pitot HC, Petrini JH, Albertson DG, Dove WF

Author

Amy Jeanette Prunuske PhD Associate Professor in the Medical School Regional Campuses department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Adenoma
Adenomatous Polyposis Coli Protein
Alkylating Agents
Animals
Cell Cycle Proteins
DNA-Binding Proteins
Disease Models, Animal
Disease Progression
Ethylnitrosourea
Feces
Female
Helicobacter Infections
Helicobacter pylori
Humans
Intestinal Neoplasms
Intestines
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mutation
Nuclear Proteins
Signal Transduction
Survival Analysis
Time Factors
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a