Paradoxes of the EphB4 Receptor in Cancer
Open Access
- 1 May 2007
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (9), 3994-3997
- https://doi.org/10.1158/0008-5472.can-07-0525
Abstract
Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogen-induced changes in gene expression. Male Eker and wild-type rats were gavaged daily with AA (10 mg/kg body weight) or OTA (210 μg/kg body weight). After 1, 3, 7, and 14 days of exposure, renal histopathology, tubular cell proliferation, and Affymetrix gene expression profiles from renal cortex/outer medulla were analyzed. AA-treated Eker and wild-type rats were qualitatively comparable in all variables assessed, suggesting a Tsc2-independent mechanism of action. OTA treatment resulted in slightly increased cortical pathology and significantly elevated cell proliferation in both strains, although Eker rats were more sensitive. Deregulated genes involved in the phosphatidylinositol 3-kinase-AKT-Tsc2-mammalian target of rapamycin signaling, among other important genes prominent in tumorigenesis, in conjunction with the enhanced cell proliferation and presence of preneoplastic lesions suggested involvement of Tsc2 in OTA-mediated toxicity and carcinogenicity, especially as deregulation of genes involved in this pathway was more prominent in the Tsc2 mutant Eker rat. [Cancer Res 2007;67(9):4052–68]Keywords
This publication has 27 references indexed in Scilit:
- EPHB4 and Survival of Colorectal Cancer PatientsCancer Research, 2006
- Eph tumour suppression: the dark side of GleevecNature, 2006
- Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast CancerThe American Journal of Pathology, 2006
- Disruption of EphA2 Receptor Tyrosine Kinase Leads to Increased Susceptibility to Carcinogenesis in Mouse SkinCancer Research, 2006
- EphB/EphrinB Receptors and Wnt Signaling in Colorectal CancerCancer Research, 2006
- Eph receptor signalling casts a wide net on cell behaviourNature Reviews Molecular Cell Biology, 2005
- Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancerNature Genetics, 2004
- Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffoldBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004
- Eph/Ephrin Signaling Regulates the Mesenchymal-to-Epithelial Transition of the Paraxial Mesoderm during Somite MorphogenesisCurrent Biology, 2003
- Three distinct regions of allelic loss at 13q14, 13q21-22, and 13q33 in prostate cancerGenes, Chromosomes and Cancer, 1999