Characterization of a major colon cancer susceptibility locus (Ccs3) on mouse chromosome 3
ABSTRACT Treatment of mice with the carcinogen azoxymethane (AOM) induces a number of lesions in the colon, including hyperplastic lesions, as well adenomas and carcinomas in situ. Inbred strains of mice show different responses to AOM-induced carcinogenesis. A/J mice are highly susceptible and develop a greater number of hyperplastic lesions and tumors (15-70 tumors per mouse) than resistant C57BL/6J mice (0-6 tumors per mouse). Susceptibility to AOM-induced tumors segregates as a co-dominant trait in (A x B6)F1 hybrids. Using a set of 23 AcB and BcA recombinant congenic mouse strains derived from A/J (susceptible) and B6 (resistant) parents, we observed that the number of hyperplastic lesions and tumors induced by AOM was under different genetic controls in AcB/BcA strains. The multiplicity of AOM-induced tumors is controlled by a major locus that we have mapped on the distal portion of chromosome 3, to which we have given the temporary designation colon cancer susceptibility locus 3 (Ccs3). B6 and A/J alleles at Ccs3 are associated with resistance and susceptibility, respectively. Haplotype analysis in key informative AcB/BcA strains restricts the size of the Ccs3 locus to a 14 Mb segment that contains 94 annotated genes. The expression level of all these genes in normal colon has been established by transcript profiling with microarrays, and has led to the identification of a subset of positional candidates that are expressed at high levels in this tissue. The 4q and 1p human chromosomal segments sharing syntenic homology with the mouse Ccs3 segment are known to be associated with inflammatory bowel diseases and colorectal tumors in humans, suggesting that the study of the mouse Ccs3 locus may help further the pathogenesis of these human conditions.
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ABSTRACT: Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.Immunity 11/2013; DOI:10.1016/j.immuni.2013.11.003 · 19.75 Impact Factor
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ABSTRACT: We have previously shown that the differential susceptibility of A/J (susceptible) and C57BL/6J (B6, resistant) mouse strains to azoxymethane (AOM)-induced colorectal cancer (CRC) is controlled by the chromosome 3 locus, Ccs3. We report that A/J and B6 mice also show differential susceptibility to colitis-associated colorectal cancer (CA-CRC) induced by combined administration of AOM and dextran sulfate. This differential susceptibility is not controlled by Ccs3, but is under distinct genetic control. Linkage analyses in (A/J x B6)F2 mice detected a major CA-CRC susceptibility locus on chromosome 9 (Ccs4) which controls tumor multiplicity and tumor surface area. Susceptibility alleles at Ccs4 are inherited in a recessive fashion, with A/J alleles being associated with susceptibility. We also detected a second locus on chromosome 14 that acts in an additive fashion with Ccs4. Strikingly, F2 mice homozygous for A/J alleles at both loci (Ccs4 and chromosome 14) are as susceptible to CA-CRC as the A/J controls while mice homozygous for B6 alleles are as resistant as the B6 controls, thus supporting the role of two interacting loci in this CA-CRC model. This indicates that susceptibility to chemically-induced CRC and susceptibility to CA-CRC are under distinct genetic control in mice, and probably involve distinct cellular pathways.Oncotarget 10/2010; 1(6):436-46. · 6.63 Impact Factor
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ABSTRACT: Genetic predisposition controlled by susceptibility quantitative trait loci (QTLs) contributes to a large proportion of common cancers. Studies of genetics of cancer susceptibility, however, did not address systematically the relationship between susceptibility to cancers in different organs. We present five sets of data on genetic architecture of colon and lung cancer susceptibility in mice, humans and rats. They collectively show that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related. Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes. Indeed, susceptibility to lung cancer (Sluc) loci underlying the extreme susceptibility or resistance of such CcS/Dem strains, mapped in 226 (CcS-10×CcS-19)F2 mice, co-localize with susceptibility to colon cancer (Scc) loci. Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P = 0.0036). Finally, the majority of published human and rat colon cancer susceptibility genes map to chromosomal regions homologous to mouse Sluc loci. 12/12 mouse Scc loci, 9/11 human and 5/7 rat colon cancer susceptibility loci are close to a Sluc locus or its homologous site, forming 21 clusters of lung and colon cancer susceptibility genes from one, two or three species. Our data shows that cancer susceptibility QTLs can have much broader biological effects than presently appreciated. It also demonstrates the power of mouse genetics to predict human susceptibility genes. Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.PLoS ONE 01/2011; 6(2). · 3.53 Impact Factor