Lung cancer susceptibility in Fhit-deficient mice is increased by Vhl haploinsufficiency.
The FHIT gene plays important roles in cancer development, including lung cancers, in which the Fhit protein is frequently lost. To determine if Fhit-deficient mice exhibit increased susceptibility to carcinogen-induced lung cancer, mice were treated with the pulmonary carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone. Wild-type and Fhit-deficient animals did not exhibit significantly different frequencies of lung lesions, but Fhit-/- mice showed significantly increased average tumor volume (1.62 mm3) and multiplicity in tumor-bearing mice, compared with wild-type mice (0.70 mm3). Tumors of Fhit-/- mice were all carcinomas, whereas Fhit+/+ mice did not develop carcinomas. To determine if Fhit absence, in combination with deficiency of an additional 3p tumor suppressor, would affect the frequency of tumor induction, we examined the spontaneous and dimethylnitrosamine-induced tumor phenotype of Fhit-/-Vhl+/- mice. Whereas no spontaneous lung tumors were observed in Fhit-/- or Vhl+/- mice, 44% of Fhit-/-Vhl+/- mice developed adenocarcinomas by 2 years of age. Dimethylnitrosamine (6 mg/kg body weight) induced lung tumors (adenomas and carcinomas) in 100% of Fhit-/-Vhl+/- mice and adenomas in 40% of Fhit-/- mice by 20 months of age. Thus, double deficiency in murine homologues of 3p suppressor genes, including haploinsufficiency of Vhl, predisposes to spontaneous and induced lung cancers, showing that Fhit-deficient mice will be useful, in combination with other 3p tumor suppressors, in recapitulating a pattern of lung cancer development similar to the human pattern; such double- or triple-deficient mice will be excellent lung cancer prevention and therapy models.
Zanesi
Nicola
N
Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
Mancini
Rita
R
Sevignani
Cinzia
C
Vecchione
Andrea
A
Kaou
Mohamed
M
Valtieri
Mauro
M
Calin
George A
GA
Pekarsky
Yuri
Y
Gnarra
James R
JR
Croce
Carlo M
CM
Huebner
Kay
K
D017766:Acid Anhydride Hydrolases / Q000172:deficiency* / Q000235:genetics; D000483:Alleles; D000818:Animals; D002273:Carcinogens; D003043:Cocarcinogenesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006238:Haploidy; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics; D009602:Nitrosamines; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D002273:Carcinogens; D009363:Neoplasm Proteins; D009602:Nitrosamines; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099170:Bis(5'-adenosyl)triphosphatase; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C494469:VHL protein, mouse