Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma

BMC Cancer

Research Article

Anja Van den Bussche¹  Christophe Van Steenkiste¹  Sarah Raevens¹  Lindsey Devisscher¹  Hans Van Vlierberghe¹  Annelies Paridaens¹  Eliene Bogaerts¹  Xavier Verhelst¹  Yves-Paul Vandewynckel¹  Debby Laukens¹  Anja Geerts¹  Louis Libbrecht²  Peter Carmeliet³  Bart Jonckx⁴ 

[1] Department of Hepatology and Gastroenterology, Ghent University Hospital, De Pintelaan 185, 1K12IE, B-9000, Ghent, Belgium;Department of Pathology, Ghent University Hospital, Ghent, Belgium;Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Centre, KU Leuven, Leuven, Belgium;Laboratory of Angiogenesis & Neurovascular Link, Vesalius Research Centre, VIB, Leuven, Belgium;ThromboGenics NV, Heverlee, Belgium;

关键词: Carcinoma;    Hepatocellular;    Placenta growth factor;    Tumor Microenvironment;    Unfolded protein response;    Cell hypoxia;    Angiogenesis Modulating Agents;    Hep G2 cells;   

DOI  :  10.1186/s12885-015-1990-6

 received in 2015-03-23, accepted in 2015-12-08,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. We previously showed that the inhibition of placental growth factor (PlGF) exerts antitumour effects and induces vessel normalisation, possibly reducing hypoxia. However, the exact mechanism underlying these effects remains unclear. Because hypoxia and endoplasmic reticulum stress, which activates the unfolded protein response (UPR), have been implicated in HCC progression, we assessed the interactions between PlGF and these microenvironmental stresses.MethodsPlGF knockout mice and validated monoclonal anti-PlGF antibodies were used in a diethylnitrosamine-induced mouse model for HCC. We examined the interactions among hypoxia, UPR activation and PlGF induction in HCC cells.ResultsBoth the genetic and pharmacological inhibitions of PlGF reduced the chaperone levels and the activation of the PKR-like endoplasmic reticulum kinase (PERK) pathway of the UPR in diethylnitrosamine-induced HCC. Furthermore, we identified that tumour hypoxia was attenuated, as shown by reduced pimonidazole binding. Interestingly, hypoxic exposure markedly activated the PERK pathway in HCC cells in vitro, suggesting that PlGF inhibition may diminish PERK activation by improving oxygen delivery. We also found that PlGF expression is upregulated by different chemical UPR inducers via activation of the inositol-requiring enzyme 1 pathway in HCC cells.ConclusionsPlGF inhibition attenuates PERK activation, likely by tempering hypoxia in HCC via vessel normalisation. The UPR, in turn, is able to regulate PlGF expression, suggesting the existence of a feedback mechanism for hypoxia-mediated UPR that promotes the expression of the angiogenic factor PlGF. These findings have important implications for our understanding of the effect of therapies normalising tumour vasculature.

【 授权许可】

CC BY   
© Vandewynckel et al. 2016