Epidemiologic evidence suggests that pulmonary diseases with a prominent chronic inflammatory component elevate lung cancer risk. Genetic manipulations of mouse models of lung inflammation and tumorigenesis can be used to investigate this association. The genes encoding pro-inflammatory tumor necrosis factor-α (TNFα) and anti-inflammatory IL-10 cytokines map within quantitative trait loci that regulate susceptibility to lung tumor development in mice; sensitive A/J and resistant C57BL/6J (B6) mice have different Tnfa and II-10 alleles. Genetic ablation studies were performed to examine whether these genes would qualify as candidate tumor modifiers. Tnfa null (-/-) mice on a B6 background and B6.129 II-10-/- mice were intercrossed with A/J mice and subjected to urethane carcinogenesis; lung tumor multiplicity was determined 20 weeks later. In the absence of one copy of Tnfa, tumor number. Male II-10+/+ mice developed more tumors than did female mice (P<0.001), absence of one copy of II-10 raised tumor number in female mice to that observed in +/+ males, but no change in multiplicity occurred in II-70 hemizygous males. Thus, a deficit of pro-inflammatory TNFα decreased the number of tumors, whereas diminished gene copy number of anti-inflammatory IL-10 increased tumorigenesis; manifestation of an effect of II-10 haploinsufficiency is gender dependent. These studies support a role for inflammation in lung cancer susceptibility.
- Lung tumors
- Quantitative trait loci