Age dependence of radiation-induced renal cell carcinomas in an Eker rat model.
Exposure to carcinogens early in life may contribute to cancer development later in life. The amount of radiation exposure children experience during medical procedures has been increasing, so it is important to evaluate the radiation risk of cancer in developing organs. Toward this goal, we assessed the risk of developing renal cell carcinoma using Eker rats as a kidney tumor model. F1 hybrids of male Eker (Tsc2 mutant) and female F344 rats were irradiated with 0.5 or 2 Gy gamma radiation on gestation days 15 and 19, and on postnatal days 5, 20, and 49. At 27 weeks of age, kidneys were examined for proliferative lesions. Preneoplastic lesions such as phenotypically altered tubules increased after postnatal irradiation as a function of age-at-irradiation, and hyperplasia were greatly increased after perinatal and postnatal irradiation. In contrast, development of adenoma and adenocarcinoma were evident in animals irradiated at perinatal ages, being maximal at gestational day 19. The frequency of LOH at the Tsc2 locus was unexpectedly low - 0% (0 of 4) for the unirradiated control, and 17% (6 of 35) for the irradiated group. Irrespective of LOH, the mTOR (mammalian target of rapamycin) pathway, which is negatively regulated by the Tsc1/2 complex, was activated in both benign and malignant lesions, as evidenced by phosphorylation of S6 ribosomal protein and 4E-BP1. This suggests that the wild-type Tsc2 allele may be functionally inactivated. In conclusion, actively growing kidneys in perinatal-aged (F344 x Eker) F1 rats (Tsc2(+/-)) are at risk for radiation-induced malignant transformation of the renal epithelium associated with mTOR activation.
Kokubo
Toshiaki
T
Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
Kakinuma
Shizuko
S
Kobayashi
Toshiyuki
T
Watanabe
Fumiko
F
Iritani
Riichirou
R
Tateno
Kaori
K
Nishimura
Mayumi
M
Nishikawa
Tetsu
T
Hino
Okio
O
Shimada
Yoshiya
Y
D000367:Age Factors; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000209:etiology* / Q000235:genetics; D005260:Female; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007680:Kidney Neoplasms / Q000209:etiology* / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases