Brain tumors in S100beta-v-erbB transgenic rats.
We have established a line of transgenic rats expressing v-erbB, the viral form of epidermal growth factor receptor (EGFR), under transcriptional regulation of the S100beta promoter. Reverse transcriptase-polymerase chain reaction revealed highest transgene expression in the cerebellum followed by the cerebrum, ovary, and testis. Other organs, including the lung, heart, salivary gland, colon, liver, kidney, and spleen, did not show detectable transgene expression. Of 23 homozygous rats that died or were killed because they became moribund between 25 and 91 weeks of age, 15 (65%) showed the presence of brain tumors (mean age, 59 weeks). Of the 10 heterozygous rats killed between 61 and 91 weeks of age, 4 (40%) showed the presence of brain tumors (mean, 77 weeks). With 3 exceptions, all tumors were located within or near the cerebellum (83%). There were 2 major histologic types; one type displayed a solid growth pattern with predominantly perivascular infiltration of adjacent central nervous system tissue and the meninges. Tumors showed histologic features of malignancy with occasional lung metastases. There was a consistent, strong immunoreactivity for S100 protein but no significant expression of glial, neuronal, or meningothelial markers. These tumors were classified as malignant gliomas. A second tumor type was less invasive and characterized by isomorphic cells with round to ovoid nuclei and clear perinuclear halos expressing S100 but no neuronal or glial marker proteins. They were diagnosed as oligodendrogliomas. This is the first transgenic rat model that spontaneously develops brain tumors. Because v-erbB is structurally and functionally similar to the truncated form of EGFR amplified and overexpressed in human glioblastomas, S100beta-v-erbB transgenic rats may serve as a useful animal model for the identification of EGFR-related molecular targets and as a tool for the assessment of novel therapeutic approaches.
Ohgaki
Hiroko
H
International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France. ohgaki@iarc.fr
Kita
Daisuke
D
Favereaux
Alexandre
A
Huang
Herve
H
Homma
Taku
T
Dessen
Pierre
P
Weiss
William A
WA
Kleihues
Paul
P
Heppner
Frank L
FL
D000818:Animals; D030801:Animals, Genetically Modified; D014408:Biomarkers, Tumor / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018739:Oncogene Proteins v-erbB / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D019076:Transgenes / Q000235:genetics
D014408:Biomarkers, Tumor; D009414:Nerve Growth Factors; D018739:Oncogene Proteins v-erbB; D011993:Recombinant Fusion Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins