Long-lived min mice develop advanced intestinal cancers through a genetically conservative pathway

Richard B. Halberg, Jesse Waggoner, Kristen Rasmussen, Alanna White, Linda Clipson, Amy J. Prunuske, Jeffery W. Bacher, Ruth Sullivan, Mary Kay Washington, Henry C. Pitot, John H J Petrini, Donna G. Albertson, William F. Dove

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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 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& Delta;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.

Original languageEnglish (US)
Pages (from-to)5768-5775
Number of pages8
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009

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Intestinal Neoplasms
Adenomatous Polyposis Coli
Neoplasms
Alleles
Epigenomics
Nijmegen Breakage Syndrome
Helicobacter
Microsatellite Instability
Mesentery
Genomic Instability
Mutagens
Inbred C57BL Mouse
Adenoma
Genetic Recombination
Intestines
Adenocarcinoma
Lymph Nodes
Neoplasm Metastasis
Muscles
Mutation

Cite this

Halberg, R. B., Waggoner, J., Rasmussen, K., White, A., Clipson, L., Prunuske, A. J., ... Dove, W. F. (2009). Long-lived min mice develop advanced intestinal cancers through a genetically conservative pathway. Cancer Research, 69(14), 5768-5775. https://doi.org/10.1158/0008-5472.CAN-09-0446

Long-lived min mice develop advanced intestinal cancers through a genetically conservative pathway. / Halberg, Richard B.; Waggoner, Jesse; Rasmussen, Kristen; White, Alanna; Clipson, Linda; Prunuske, Amy J.; Bacher, Jeffery W.; Sullivan, Ruth; Washington, Mary Kay; Pitot, Henry C.; Petrini, John H J; Albertson, Donna G.; Dove, William F.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5768-5775.

Research output: Contribution to journalArticle

Halberg, RB, Waggoner, J, Rasmussen, K, White, A, Clipson, L, Prunuske, AJ, Bacher, JW, Sullivan, R, Washington, MK, Pitot, HC, Petrini, JHJ, Albertson, DG & Dove, WF 2009, 'Long-lived min mice develop advanced intestinal cancers through a genetically conservative pathway', Cancer Research, vol. 69, no. 14, pp. 5768-5775. https://doi.org/10.1158/0008-5472.CAN-09-0446
Halberg RB, Waggoner J, Rasmussen K, White A, Clipson L, Prunuske AJ et al. Long-lived min mice develop advanced intestinal cancers through a genetically conservative pathway. Cancer Research. 2009 Jul 15;69(14):5768-5775. https://doi.org/10.1158/0008-5472.CAN-09-0446
Halberg, Richard B. ; Waggoner, Jesse ; Rasmussen, Kristen ; White, Alanna ; Clipson, Linda ; Prunuske, Amy J. ; Bacher, Jeffery W. ; Sullivan, Ruth ; Washington, Mary Kay ; Pitot, Henry C. ; Petrini, John H J ; Albertson, Donna G. ; Dove, William F. / Long-lived min mice develop advanced intestinal cancers through a genetically conservative pathway. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5768-5775.
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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 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& Delta;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.",
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AU - Waggoner, Jesse

AU - Rasmussen, Kristen

AU - White, Alanna

AU - Clipson, Linda

AU - Prunuske, Amy J.

AU - Bacher, Jeffery W.

AU - Sullivan, Ruth

AU - Washington, Mary Kay

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AU - Petrini, John H J

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