Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Vandewynckel, Yves-Paul; Laukens, Debby; Devisscher, Lindsey; Bogaerts, Eliene; Paridaens, Annelies; Van den Bussche, Anja; Raevens, Sarah; Verhelst, Xavier; Van Steenkiste, Christophe; Jonckx, Bart; Libbrecht, Louis; Geerts, Anja; Carmeliet, Peter; Van Vlierberghe, Hans
• Is Part Of: BMC cancer. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 10
• Publication Date: 2016-12
• Subjects: Carcinoma -- Hepatocellular -- Placenta growth factor -- Tumor Microenvironment -- Unfolded protein response -- Cell hypoxia -- Angiogenesis Modulating Agents -- Hep G2 cells; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-015-1990-6
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background Hepatocellular 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. Methods PlGF 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. Results Both 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 cellsin 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. Conclusions PlGF 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.