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-b (TGF-b) 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-b receptors by PDGF-B. Additionally, overexpression of PDGF-B also leads to an increased expression of b-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.

Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

“…Dissecting the effect of Asp/Clo on all these factors in our system is beyond the scope of this report. It is worth mentioning, however, that PDGF and serotonin have been reported to support HCC development in mice exposed to diethylnitrosamine (31) or to CCl 4 (32), respectively, two situations in which carcinogenesis is independent of adaptive immune responses and, as shown here for CCl 4 -treated mice, might not be influenced by antiplatelet therapy. Although indirectly, this may argue against the hypothesis that Asp/Clo-dependent amelioration of HCC in mice with immune-mediated chronic hepatitis reflects inhibition of PDGF-and serotonin-dependent pathways.…”

Platelet-Derived Growth Factor Regulates Breast Cancer Progression via β-Catenin Expression

“…Because PDGF also activates the PI-3 kinase and Ras-MAPK pathways [31] , PDGF-BB may induce de novo synthesis of ␤ -catenin via these pathways. Furthermore, Maass et al [32] reported that PDGF-B overexpression induces ␤ -catenin upregulation in the liver. These reports suggest that ␤ -catenin upregulation was induced by PDGF-B also in breast cancer cells.…”

Vaccination with Platelet-Derived Growth Factor B Kinoids Inhibits CCl4-Induced Hepatic Fibrosis in Mice

“…Furthermore, it has been reported that PDGF-B signaling accelerates the carcinogenesis in the fibrotic livers (Maass et al, 2011). Therefore, vaccination against PDGF-B for chronic liver diseases might have dual benefits of both suppressing fibrosis and preventing carcinogenesis.…”