Studies on lung tumours. V. Susceptibility of mice to dimethylnitrosamine‐induced tumour formation in relation to H‐2 haplotype

Abstract

Male mice of the strain A/Sn, of its congeneic partner strain A.SW, C57BL/10ScSnA (abbreviated: B10), and of two congeneic strains on a B10 background (B10.A and B10.AKM) were investigated for their susceptibility to lung tumour induction by dimethylnitrosamine (DMN) administered either by intraperitoneal injection or in the drinking water. Strain B10 (haplotype H-2b) proved to be very resistant, whereas strains A/Sn (H-2a) and A.SW (H-2s) were highly susceptible. The introduction of the haplotypes H-2a and H-2m in the resistant strain B10 resulted in a significant increase in sensitivity towards DMN-induced lung tumour formation. Lung tumour incidences in male (B10.A x B10)F hybrids, receiving DMN in drinking water, were found to be intermediate between, and significantly different from, the incidences of identically-treated parent strains B10.A and B10. Males of back-cross (B10.A x B10) x B10 BC proved to be of low susceptibility to lung tumour formation by DMN, tumour incidence being very low and not significantly different from that observed in identically-treated B10 males. It is concluded that, at least in the model system of B10-derived congeneic strains, H-2 haplotype is one of the factors important in determining susceptibility towards DMN-induced lung tumours. Comparison of C3Hf (H-2k), C3H/Sn (H-2k) and the latter's congeneic strains C3H.B10 (H-2b) and C3H.NB (H-2p) of male mice showed that these strains were moderately susceptible to both lung tumour and hepatoma formation by DMN. Accordingly, the presence of an H-2 haplotype from a lung-tumour-resistant strain (H-2b, B10) on the background of a strain of intermediate susceptibility (C3H) does not decrease susceptibility to lung tumour formation. The results were considered in the light of the H-2 haplotype dependence of spontaneous lung tumours, and consequently attention has been paid to the histological types of the induced and spontaneous lung tumours.

Lung Cancer Susceptibility in Fhit-Deficient Mice Is Increased by Vhl Haploinsufficiency

“…(36) is the most potent carcinogen of several common environmental nitrosamines (37). It induces lung tumors in mice (38) and was used in this experiment to verify sensitivity to lung tumor induction in different genotypes. Dimethylnitrosamine treatment revealed that Fhit À/À Vhl +/À mice are more sensitive to chemically induced lung carcinogenesis than Fhit knockout mice.…”

At least four genes and sex are associated with susceptibility to urethane-induced pulmonary adenomas in mice

“…Congenic mouse strains with different H2 haplotypes also vary in the incidence and number of spontaneous and chemically induced lung tumours (Smith & Walford, 1976;Faraldo et al 1979;den Engelse et al 1981;Miyashita et al 1989), suggesting that the H2 region on chromosome 17 contains a second Pas gene. The identity of this gene has not been established, though Oomen et al (1989) suggested that it may be associated with the glucocorticoid receptor gene that is encoded in this region.…”

Tnfa and Il‐10 deficiencies have contrasting effects on lung tumor susceptibility: Gender‐dependent modulation of IL‐10 haploinsufficiency

“…Inbred mouse strains vary in their susceptibility to spontaneous and chemically induced lung tumor development [7,8]. Chromosomal locations of genes that regulate the outcome of tumorigenesis have been assigned by linkage analysis employing congenic strains [9,10], recombinant inbred (RI) strains [11,12], recombinant congenic strains [13], and mapping by quantitative trait locus (QTL) analysis [14]. It is highly likely that the Kras proto‐oncogene is the pulmonary adenoma susceptibility 1 ( Pas1 ) site on Chr 6 that accounts for 60–70% of the differential proclivities to lung cancer of sensitive A/J and resistant C57BL/6J (B6) mice [12,14–16].…”

“…Pas2 maps to the H‐2 region on Chr 17 and accounts for an additional 8% (as determined by QTL analysis of RI strains) or 14% (determined by QTL analysis of F2 mice) of the difference in susceptibility to lung tumorigenesis between A/J and B6 mice [15]. Additional evidence that Pas2 modifies responsiveness to the Kras polymorphism includes studies in which A/J mice congenic for the B6 H–2 region, designated A/J H‐2(b) , are more resistant to lung tumorigenesis than A/J mice, whereas B6 mice congenic for H‐2(a) , designated B6 H‐2(a) , are more sensitive [9,10]. The site with highest linkage with lung tumor formation within H‐2 is at Tnfa [12], a gene encoding a pro‐inflammatory cytokine to which lung epithelial cells respond [23].…”