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

Yves-Paul Vandewynckel, Debby Laukens UGent, Lindsey Devisscher UGent, Eliene Bogaerts, Annelies Paridaens, Anja Van den Bussche, Sarah Raevens UGent, Xavier Verhelst UGent, Christophe Van Steenkiste UGent, Bart Jonckx, et al. (2016) BMC CANCER. 16.
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 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. 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
RECEPTOR, Carcinoma, MOUSE MODEL, TUMOR-GROWTH, ER-STRESS, Hep G2 cells, Angiogenesis Modulating Agents, Unfolded protein response, Cell hypoxia, Hepatocellular, Placenta growth factor, Tumor Microenvironment, ANGIOGENESIS, ACTIVATION, FLT-1, TARGETS, PATHWAY, PLGF
journal title
BMC CANCER
BMC Cancer
volume
16
article number
9
pages
10 pages
Web of Science type
Article
Web of Science id
000368076600001
JCR category
ONCOLOGY
JCR impact factor
3.288 (2016)
JCR rank
93/217 (2016)
JCR quartile
2 (2016)
ISSN
1471-2407
DOI
10.1186/s12885-015-1990-6
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
7063955
handle
http://hdl.handle.net/1854/LU-7063955
date created
2016-01-31 00:24:03
date last changed
2016-12-21 15:41:53
@article{7063955,
  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 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. 
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.},
  articleno    = {9},
  author       = {Vandewynckel, Yves-Paul and Laukens, Debby and Devisscher, Lindsey and Bogaerts, Eliene and Paridaens, Annelies and Van den Bussche, Anja and Raevens, Sarah and Verhelst, Xavier and Van Steenkiste, Christophe and Jonckx, Bart and Libbrecht, Louis and Geerts, Anja and Carmeliet, Peter and Van Vlierberghe, Hans},
  issn         = {1471-2407},
  journal      = {BMC CANCER},
  keyword      = {RECEPTOR,Carcinoma,MOUSE MODEL,TUMOR-GROWTH,ER-STRESS,Hep G2 cells,Angiogenesis Modulating Agents,Unfolded protein response,Cell hypoxia,Hepatocellular,Placenta growth factor,Tumor Microenvironment,ANGIOGENESIS,ACTIVATION,FLT-1,TARGETS,PATHWAY,PLGF},
  language     = {eng},
  pages        = {10},
  title        = {Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma},
  url          = {http://dx.doi.org/10.1186/s12885-015-1990-6},
  volume       = {16},
  year         = {2016},
}

Chicago
Vandewynckel, Yves-Paul, Debby Laukens, Lindsey Devisscher, Eliene Bogaerts, Annelies Paridaens, Anja Van den Bussche, Sarah Raevens, et al. 2016. “Placental Growth Factor Inhibition Modulates the Interplay Between Hypoxia and Unfolded Protein Response in Hepatocellular Carcinoma.” Bmc Cancer 16.
APA
Vandewynckel, Y.-P., Laukens, D., Devisscher, L., Bogaerts, E., Paridaens, A., Van den Bussche, A., Raevens, S., et al. (2016). Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma. BMC CANCER, 16.
Vancouver
1.
Vandewynckel Y-P, Laukens D, Devisscher L, Bogaerts E, Paridaens A, Van den Bussche A, et al. Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma. BMC CANCER. 2016;16.
MLA
Vandewynckel, Yves-Paul, Debby Laukens, Lindsey Devisscher, et al. “Placental Growth Factor Inhibition Modulates the Interplay Between Hypoxia and Unfolded Protein Response in Hepatocellular Carcinoma.” BMC CANCER 16 (2016): n. pag. Print.