Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse

Biozzi, G; Ribeiro, Orlando; Saran, Anna; Araújo, Maria Leonor Oliveira; Maria, Durvanei Augusto; Franco, Marcelo De; Cabrera, Wafa K.; Sant’Anna, Osvaldo A.; Massa, Solange; Covelli, Vincenzo; Mouton, D; Neveu, T; Siqueira, Maria; Ibañez, Olga M.

doi:10.1093/carcin/19.2.337

Cited by 98 publications

(137 citation statements)

References 36 publications

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“…Studies carried out during the selective process of AIRmax and AIRmin lines, in F1 (AIRmax Â AIRmin) hybrids, and in F2 intercross populations 26 suggest the involvement of seven and 11 QTL controlling protein and cell influx, respectively. As mentioned previously, the Slc11a1 gene region could be one of these QTL.…”

Section: Discussionmentioning

confidence: 99%

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

et al. 2006

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Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) gene. In order to study the interactions of the Slc11a1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmax RR , AIRmax SS , AIRmin RR and AIRmin SS lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmax RR mice reached 29%, whereas PIA incidence in AIRmax SS mice was 70% by day 180. AIRmin RR mice were resistant, whereas 13.3% of AIRmin SS mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in Slc11a1 SS mice was observed. These results indicate that Slc11a1 is a strong candidate for the QTL modulating acute inflammation and for PIA.

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Section: Discussionmentioning

confidence: 99%

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

et al. 2006

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“…Given that different macrophage populations utilize different receptors for the engulfment of apoptotic cells [218], and that death induced by different agents causes cells to be recognized differently by macrophages or non-professional phagocytes [219], these observations suggest highly variable inflammatory-type responses to cell damage in different tissues and different genotypes. Evidence that these can be directly associated with tumourigenesis has come from studies of mice bred for different inflammatory responses that show different tumour susceptibilities and metastatic properties of tumours [220][221][222], culminating in the recent identification that the previously identified murine susceptibility locus for lung tumourigenesis, Pas1, affects inflammatory responses [223]. In addition, a recent study designed to identify modifiers of macrophage activation that act as tumour susceptibility genes has identified and partially mapped three such loci [224].…”

Section: Genetic Factors Influencing Genotoxic Responses and Tumourigmentioning

confidence: 99%

Cell and tissue responses to genotoxic stress

Coates

Lorimore

Wright

2005

The Journal of Pathology

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Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell-and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell-and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell-and tissuespecific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell-and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

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“…Mice with the maximum acute inflammatory reaction (AIRmax) are significantly more resistant than minimum responders (AIRmin) to two-stage skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) followed by repeated doses of the promoter agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA), 2 and also to lung carcinogenesis induced by urethane, 3 suggesting that a subset of loci affecting the inflammatory response also act as cancer modifier loci.…”

mentioning

confidence: 99%

Aryl hydrocarbon receptor polymorphism modulates DMBA‐induced inflammation and carcinogenesis in phenotypically selected mice

Souza

Cabrera

Galvan

et al. 2008

Intl Journal of Cancer

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We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1b, Tnf, Il6, Tgfb1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high-affinity ligand-binding receptor (Ahr b1 ), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low-affinity binding receptor Key words: aryl hydrocarbon receptor; DMBA; inflammation; carcinogenesis; selected mice Two nonisogenic mouse lines derived by bidirectional selection based on the intensity of local acute inflammatory reactions (AIR) to polyacrylamide beads (Biogel) 1 have shown striking differences in resistance/susceptibility to chemical-induced carcinogenesis. Mice with the maximum acute inflammatory reaction (AIRmax) are significantly more resistant than minimum responders (AIRmin) to two-stage skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) followed by repeated doses of the promoter agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA), 2 and also to lung carcinogenesis induced by urethane, 3 suggesting that a subset of loci affecting the inflammatory response also act as cancer modifier loci.DMBA and other polycyclic aromatic hydrocarbon compounds (PAHs) exert carcinogenic effects following metabolic activation mediated by the intracellular aryl hydrocarbon receptor (Ahr), a ligand-activated transcriptional factor regulating the induction of mono-oxygenase enzymes that convert the parent DMBA compound to a diol epoxide, the actual carcinogenic moiety. 4 Ahr gene presents functional polymorphism, which accounts for differences in responses of mouse strains to PAHs. 5 We investigated DMBA-induced skin contact reactions and skin and lung tumor development in AIR mice with respect to their allele status of the Ahr gene. Our results implicate Ahr in tumor susceptibility and in inflammatory response control in AIRmax and AIRmin mice. Material and methods Mice and tumor inductionAIRmax and AIRmin mice from the 38th generation of selective breedings were produced at Laboratory of Immunogenetics of Butantan Institute (São Paulo, Brazil). All experimental procedures were approved by the Animal Experimentation Ethics Committee of the Institute. Doses of 50 lg DMBA (Sigma, St. Louis, MO) in 0.1 ml acetone were applied to the shaved dorsal skin of mice during 5 consecutive days. Skin tumors were scored twice a week in groups of 15 AIRmax and 15 AIRmi...

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Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse

Cited by 98 publications

References 36 publications

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

Cell and tissue responses to genotoxic stress

Aryl hydrocarbon receptor polymorphism modulates DMBA‐induced inflammation and carcinogenesis in phenotypically selected mice

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