Polyclonality of familial murine adenomas: analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions.

Thliveris AT, Halberg RB, Clipson L, Dove WF, Sullivan R, Washington MK, Stanhope S, Newton MA
Proc Natl Acad Sci U S A. 2005 102 (19): 6960-5

PMID: 15870186 · PMCID: PMC1100801 · DOI:10.1073/pnas.0502662102

In previous studies demonstrating the polyclonal structure of familial intestinal adenomas, high tumor multiplicity made it difficult to eliminate the possibility that polyclonality arose by the random collision of distinct initiated clones as opposed to some form of clonal interaction. We sought to test further the random collision hypothesis. Chimeric mice carrying the multiple intestinal neoplasia (Min) mutation of the adenomatous polyposis coli gene (Apc) and homozygous for the tumor resistance allele of the Mom1 locus were established. These chimeras also display a strong propensity for tumors of polyclonal structure, despite their markedly reduced tumor multiplicity. Considering tumor sizes and multiplicities, the observed fraction of overtly polyclonal heterotypic adenomas was significantly higher than predicted by the random collision hypothesis. This finding supports models of polyclonality involving interaction among multiple initiated clones. The extent of clonal interaction was assessed by statistical analyses that relate the observed frequency of overtly polyclonal heterotypic tumors to the geometry of the chimeric patches and the pattern of underlying crypts. These statistical calculations indicate that the familial adenomas of the Apc(Min/+) mouse may commonly form through interactions between clones as close as 1-2 crypt diameters apart.

MeSH Terms (21)

Adenoma Adenomatous Polyposis Coli Adenomatous Polyposis Coli Protein Alleles Animals Chimera Computational Biology Crosses, Genetic Disease Progression Genes, APC Homozygote Immunohistochemistry Mice Mice, Transgenic Models, Genetic Models, Molecular Models, Statistical Mutation Phenotype Software Transgenes

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