Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC.
Mlh1-knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1-/- mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein. Irradiation of 10-week-old Mlh1-/- mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/- and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1-/- mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1-/- mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.
Tokairin
Yutaka
Y
Department of Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8510, Japan. y_tokai.srg2@tmd.ac.jp
Kakinuma
Shizuko
S
Arai
Masami
M
Nishimura
Mayumi
M
Okamoto
Mieko
M
Ito
Eisaku
E
Akashi
Makoto
M
Miki
Yoshio
Y
Kawano
Tatsuyuki
T
Iwai
Takehisa
T
Shimada
Yoshiya
Y
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000209:etiology; D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D004195:Disease Models, Animal; D018450:Disease Progression; D005770:Gastrointestinal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D052138:Genes, Neoplasm / Q000235:genetics; D007150:Immunohistochemistry / Q000379:methods; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D011878:Radiotherapy / Q000009:adverse effects; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D013953:Thymus Neoplasms / Q000209:etiology; D016212:Transforming Growth Factor beta / Q000032:analysis; D053781:Transforming Growth Factor beta2; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051176:beta Catenin / Q000032:analysis
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D000070957:MutL Protein Homolog 1