Carcinogenesis, Vol 19, 337-346, Copyright © 1998 by Oxford University Press
G Biozzi, OG Ribeiro, A Saran, ML Araujo, DA Maria, M De Franco, WK Cabrera, OA Sant'anna, S Massa, V Covelli, D Mouton, T Neveu, M Siqueira and OM Ibanez
Two distinct bidirectional selective breedings for quantitative traits were
initiated from identical genetically heterogeneous mouse populations. The
resulting lines are characterized by maximal or minimal acute inflammatory
responsiveness (AIR): AIRmax and AIRmin lines, respectively, and by
resistance or susceptibility to chemical skin tumorigenesis: Car-R and
Car-S lines, respectively. The AIR response to s.c. injection of
polyacrylamide microbeads, measured by cell content in the local exudate,
was 10 times higher in AIRmax than in AIRmin mice. The response to
selection was asymmetrical: the realized heritability was 0.26 in AIRmax
and 0.008 in AIRmin, and resulted from the additive effect of 7-11
quantitative trait loci (QTL). Low responsiveness was globally dominant in
F1 and 48% of F2 segregant variance was found to be due to genetic factors.
These findings are the first demonstration of innate regulation of AIR by
germ line genes. Susceptibility to skin tumorigenesis induced by a two-
stage initiation (DMBA)-promotion (TPA) protocol was lower in AIRmax mice
than in AIRmin mice, a 6-fold difference in tumor induction rate. Intense
AIR was found to be associated with resistance, and low AIR with
susceptibility to tumorigenesis, in F2 segregants chosen for extreme AIR
phenotypes. At least some of the AIR QTLs therefore contain genes
controlling tumorigenesis. Tumor phenotypes differed more in Car- R and
Car-S than in AIRmax and AIRmin lines, indicating that QTLs unrelated to
AIR, contribute to the host response to tumorigenesis. The extreme
phenotypes/genotypes of the four selected lines and the known genetic
constitution of their foundation population, offer new possibilities to
discriminate the genes/mechanisms controlling two important traits: AIR and
response to chemical tumorigenesis. Collaborative projects will be
favorably considered. The description of tumor resistance genes in AIRmax
and Car-R mice may be helpful for epidemiology and therapy of human cancer.
REVIEWS
Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse
Unite 255 INSERM, Institut Curie, Paris, France. dmouton@curie.fr
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