title: Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis.
abstract: A genetic basis of hepatocellular carcinoma (HCC) has been well-established and major signaling pathways, such as p53, Wnt-signaling, transforming growth factor-β (TGF-β) and Ras pathways, have been identified to be essential to HCC development. Lately, the family of platelet-derived growth factors (PDGFs) has shifted to the center of interest. We have reported on spontaneously developing liver fibrosis in PDGF-B transgenic mice. Since HCC rarely occurs in healthy liver, but dramatically increases at the cirrhosis stage of which liver fibrosis is a preliminary stage, we investigated liver cancer development in chemically induced liver carcinogenesis in these mice. HCC induction was performed by treatment of the mice with diethylnitrosamine and phenobarbital. At an age of 6 months, the tumor development of these animals was analyzed. Not only the development of dysplastic lesions in PDGF-B transgenic mice was significantly increased but also their malignant transformation to HCC. Furthermore, we were able to establish a key role of PDGF-B signaling at diverse stages of liver cancer development. Here, we show that development of liver fibrosis is likely through upregulation of TGF-β receptors by PDGF-B. Additionally, overexpression of PDGF-B also leads to an increased expression of β-catenin as well as vascular endothelial growth factor and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), all factors with established roles in carcinogenesis. We were able to extend the understanding of key genetic regulators in HCC development by PDGF-B and decode essential downstream signals.
authors.affiliation: Department of Medicine I, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maass
authors.forename: Florian R
authors.initials: FR
authors.lastname: Thieringer
authors.forename: Amrit
authors.initials: A
authors.lastname: Mann
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.forename: Torsten
authors.initials: T
authors.lastname: Hansen
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.forename: Stephan
authors.initials: S
authors.lastname: Kanzler
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004052:Diethylnitrosamine / Q000633:toxicity; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010634:Phenobarbital / Q000633:toxicity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000927:Anticonvulsants; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004052:Diethylnitrosamine; D005346:Fibroblast Growth Factors; D010634:Phenobarbital