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

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Vandewynckel, Yves-Paul Laukens, Debby Devisscher, Lindsey Bogaerts, Eliene Paridaens, Annelies Libbrecht, Louis [UCL] Van Vlierberghe, Hans

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2016
Language Anglais
Journal information "BMC Cancer" - Vol. 16, no.1, p. 9 [1-10] (2016)
Peer reviewed yes
Publisher BioMed Central Ltd. ((United Kingdom) London)
e-issn 1471-2407
Publication status Publié
Affiliations UCL - SSS/IREC/SLUC - Pôle St.-Luc
UCL - (SLuc) Service d'anatomie pathologique
MESH Subject Animals ; Humans ; Liver Neoplasms ; Mice ; Mice, Knockout ; Neovascularization, Pathologic ; Placenta Growth Factor ; Pregnancy Proteins ; Tumor Microenvironment ; Unfolded Protein Response ; eIF-2 Kinase ; Carcinoma, Hepatocellular ; Cell Hypoxia ; Diethylnitrosamine ; Disease Models, Animal ; Endoplasmic Reticulum Stress ; Gene Expression Regulation, Neoplastic ; Glycosaminoglycans ; Hep G2 Cells
Keywords Carcinoma ; Hepatocellular ; Placenta growth factor ; Tumor Microenvironment ; Unfolded protein response ; Cell hypoxia ; Angiogenesis Modulating Agents ; Hep G2 cells
Links
  1. International Agency for Research on Cancer. GLOBOCAN 2012. Estimated Incidence, Mortality and Prevalence Worldwide in 2012. Available at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx . Accessed 12 December 2014.
  2. , , EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma, 10.1016/j.jhep.2011.12.001
  3. Coulon Stephanie, Heindryckx Femke, Geerts Anja, Van Steenkiste Christophe, Colle Isabelle, Van Vlierberghe Hans, Angiogenesis in chronic liver disease and its complications : Angiogenesis in CLD, 10.1111/j.1478-3231.2010.02369.x
  4. De Falco Sandro, The discovery of placenta growth factor and its biological activity, 10.3858/emm.2012.44.1.025
  5. Van de Veire Sara, Stalmans Ingeborg, Heindryckx Femke, Oura Hajimu, Tijeras-Raballand Annemilaï, Schmidt Thomas, Loges Sonja, Albrecht Imke, Jonckx Bart, Vinckier Stefan, Van Steenkiste Christophe, Tugues Sònia, Rolny Charlotte, De Mol Maria, Dettori Daniela, Hainaud Patricia, Coenegrachts Lieve, Contreres Jean-Olivier, Van Bergen Tine, Cuervo Henar, Xiao Wei-Hong, Le Henaff Carole, Buysschaert Ian, Masouleh Behzad Kharabi, Geerts Anja, Schomber Tibor, Bonnin Philippe, Lambert Vincent, Haustraete Jurgen, Zacchigna Serena, Rakic Jean-Marie, Jiménez Wladimiro, Noël Agnes, Giacca Mauro, Colle Isabelle, Foidart Jean-Michel, Tobelem Gerard, Morales-Ruiz Manuel, Vilar José, Maxwell Patrick, Vinores Stanley A., Carmeliet Geert, Dewerchin Mieke, Claesson-Welsh Lena, Dupuy Evelyne, Van Vlierberghe Hans, Christofori Gerhard, Mazzone Massimiliano, Detmar Michael, Collen Désiré, Carmeliet Peter, Further Pharmacological and Genetic Evidence for the Efficacy of PlGF Inhibition in Cancer and Eye Disease, 10.1016/j.cell.2010.02.039
  6. Fischer Christian, Jonckx Bart, Mazzone Massimiliano, Zacchigna Serena, Loges Sonja, Pattarini Lucia, Chorianopoulos Emmanuel, Liesenborghs Laurens, Koch Marta, De Mol Maria, Autiero Monica, Wyns Sabine, Plaisance Stephane, Moons Lieve, van Rooijen Nico, Giacca Mauro, Stassen Jean-Marie, Dewerchin Mieke, Collen Desire, Carmeliet Peter, Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels, 10.1016/j.cell.2007.08.038
  7. Li Tao, Zhu Yuhua, Qin Cheng-yong, Yang Zhen, Fang Aiju, Xu Shifeng, Ren Wanhua, Expression and prognostic significance of vascular endothelial growth factor receptor 1 in hepatocellular carcinoma, 10.1136/jclinpath-2012-200721
  8. Ng Irene O.L., Poon Ronnie T.P., Lee Joyce M.F., Fan Sheung T., Ng Matthew, Tso Wai K., Microvessel Density, Vascular Endothelial Growth Factor and Its Receptors Flt-1 and Flk-1/KDR in Hepatocellular Carcinoma, 10.1309/fxnl-qtn1-94fh-ab3a
  9. Heindryckx Femke, Coulon Stephanie, Terrie Ellen, Casteleyn Christophe, Stassen Jean-Marie, Geerts Anja, Libbrecht Louis, Allemeersch Joke, Carmeliet Peter, Colle Isabelle, Van Vlierberghe Hans, The placental growth factor as a target against hepatocellular carcinoma in a diethylnitrosamine-induced mouse model, 10.1016/j.jhep.2012.09.032
  10. Fischer Christian, Mazzone Massimiliano, Jonckx Bart, Carmeliet Peter, FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?, 10.1038/nrc2524
  11. Bais Carlos, Wu Xiumin, Yao Jenny, Yang Suya, Crawford Yongping, McCutcheon Krista, Tan Christine, Kolumam Ganesh, Vernes Jean-Michel, Eastham-Anderson Jeffrey, Haughney Peter, Kowanetz Marcin, Hagenbeek Thijs, Kasman Ian, Reslan Hani Bou, Ross Jed, Van Bruggen Nick, Carano Richard A.D., Meng Yu-Ju Gloria, Hongo Jo-Anne, Stephan Jean- Philippe, Shibuya Masabumi, Ferrara Napoleone, PlGF Blockade Does Not Inhibit Angiogenesis during Primary Tumor Growth, 10.1016/j.cell.2010.01.033
  12. Lassen U, Nielsen DL, Sørensen M, Winstedt L, Niskanen T, Stenberg Y, et al. A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours. Br J Cancer. 2012;106:678–84.
  13. Vandewynckel Y-P, Laukens D, Geerts A, Bogaerts E, Paridaens A, Verhelst X, et al. The paradox of the unfolded protein response in cancer. Anticancer Res. 2013;33:4683–94.
  14. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89–102.
  15. Vandewynckel Yves-Paul, Laukens Debby, Bogaerts Eliene, Paridaens Annelies, Van den Bussche Anja, Verhelst Xavier, Van Steenkiste Christophe, Descamps Benedicte, Vanhove Chris, Libbrecht Louis, De Rycke Riet, Lambrecht Bart N., Geerts Anja, Janssens Sophie, Van Vlierberghe Hans, Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy, 10.1007/s12072-014-9582-0
  16. Shuda Masahiro, Kondoh Nobuo, Imazeki Nobuo, Tanaka Kenji, Okada Tetsuya, Mori Kazutoshi, Hada Akiyuki, Arai Masaaki, Wakatsuki Toru, Matsubara Osamu, Yamamoto Naoki, Yamamoto Mikio, Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis, 10.1016/s0168-8278(03)00029-1
  17. Han Jaeseok, Back Sung Hoon, Hur Junguk, Lin Yu-Hsuan, Gildersleeve Robert, Shan Jixiu, Yuan Celvie L., Krokowski Dawid, Wang Shiyu, Hatzoglou Maria, Kilberg Michael S., Sartor Maureen A., Kaufman Randal J., ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death, 10.1038/ncb2738
  18. Shoulders Matthew D., Ryno Lisa M., Genereux Joseph C., Moresco James J., Tu Patricia G., Wu Chunlei, Yates John R., Su Andrew I., Kelly Jeffery W., Wiseman R. Luke, Stress-Independent Activation of XBP1s and/or ATF6 Reveals Three Functionally Diverse ER Proteostasis Environments, 10.1016/j.celrep.2013.03.024
  19. Carmeliet Peter, Moons Lieve, Luttun Aernout, Vincenti Valeria, Compernolle Veerle, De Mol Maria, Wu Yan, Bono Françoise, Devy Laetitia, Beck Heike, Scholz Dimitri, Acker Till, DiPalma Tina, Dewerchin Mieke, Noel Agnes, Stalmans Ingeborg, Barra Adriano, Blacher Sylvia, Vandendriessche Thierry, Ponten Annica, Eriksson Ulf, Plate Karl H., Foidart Jean-Michel, Schaper Wolfgang, Charnock-Jones D. Stephen, Hicklin Daniel J., Herbert Jean-Marc, Collen Désiré, Persico M. Graziella, 10.1038/87904
  20. Heindryckx Femke, Mertens Koen, Charette Nicolas, Vandeghinste Bert, Casteleyn Christophe, Van Steenkiste Christophe, Slaets Dominique, Libbrecht Louis, Staelens Steven, Starkel Peter, Geerts Anja, Colle Isabelle, Van Vlierberghe Hans, Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma, 10.1186/1476-4598-9-219
  21. Yang Xiaojuan, Zhang Yin, Yang Yunlong, Lim Sharon, Cao Ziquan, Rak Janusz, Cao Yihai, Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth, 10.1073/pnas.1309629110
  22. Riedl Christopher C., Brader Peter, Zanzonico Pat B., Chun Yun Shin, Woo Yanghee, Singh Paramjeet, Carlin Sean, Wen Bixiu, Ling C. Clifton, Hricak Hedvig, Fong Yuman, Imaging Hypoxia in Orthotopic Rat Liver Tumors with Iodine 124–labeled Iodoazomycin Galactopyranoside PET, 10.1148/radiol.2482071421
  23. Errico Michela, Riccioni Teresa, Iyer Shalini, Pisano Claudio, Acharya K. Ravi, Persico M. Graziella, De Falco Sandro, Identification of Placenta Growth Factor Determinants for Binding and Activation of Flt-1 Receptor, 10.1074/jbc.m401418200
  24. Hedlund E.-M. E., Yang X., Zhang Y., Yang Y., Shibuya M., Zhong W., Sun B., Liu Y., Hosaka K., Cao Y., Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs, 10.1073/pnas.1209310110
  25. Maes Hannelore, Kuchnio Anna, Peric Aleksandar, Moens Stijn, Nys Kris, De Bock Katrien, Quaegebeur Annelies, Schoors Sandra, Georgiadou Maria, Wouters Jasper, Vinckier Stefan, Vankelecom Hugo, Garmyn Marjan, Vion Anne-Clémence, Radtke Freddy, Boulanger Chantal, Gerhardt Holger, Dejana Elisabetta, Dewerchin Mieke, Ghesquière Bart, Annaert Wim, Agostinis Patrizia, Carmeliet Peter, Tumor Vessel Normalization by Chloroquine Independent of Autophagy, 10.1016/j.ccr.2014.06.025
  26. Rachidi Saleh, Sun Shaoli, Wu Bill X., Jones Elizabeth, Drake Richard R., Ogretmen Besim, Cowart L. Ashley, Clarke Christopher J., Hannun Yusuf A., Chiosis Gabriela, Liu Bei, Li Zihai, Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis, 10.1016/j.jhep.2014.11.010
  27. Choi Sung Hoon, Kwon Oh-Joon, Park Jun Yong, Kim Do Young, Ahn Sang Hoon, Kim Seung Up, Ro Simon Weonsang, Kim Kyung Sik, Park Jeon Han, Kim Seungtaek, Yun Chae-Ok, Han Kwang-Hyub, Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma, 10.1111/liv.12375
  28. Hou Xu, Liu Yaohua, Liu Huailei, Chen Xin, Liu Min, Che Hui, Guo Fei, Wang Chunlei, Zhang Daming, Wu Jianing, Chen Xiaofeng, Shen Chen, Li Chenguang, Peng Fei, Bi Yunke, Yang Zhuowen, Yang Guang, Ai Jing, Gao Xin, Zhao Shiguang, PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation, 10.1038/srep09065
  29. Mujcic H., Nagelkerke A., Rouschop K. M. A., Chung S., Chaudary N., Span P. N., Clarke B., Milosevic M., Sykes J., Hill R. P., Koritzinsky M., Wouters B. G., Hypoxic Activation of the PERK/eIF2  Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3, 10.1158/1078-0432.ccr-13-0526
  30. Van Steenkiste Christophe, Ribera Jordi, Geerts Anja, Pauta Montse, Tugues Sònia, Casteleyn Christophe, Libbrecht Louis, Olievier Kim, Schroyen Ben, Reynaert Hendrik, van Grunsven Leo A., Blomme Bram, Coulon Stephanie, Heindryckx Femke, De Vos Martine, Stassen Jean Marie, Vinckier Stefan, Altamirano Jose, Bataller Ramón, Carmeliet Peter, Van Vlierberghe Hans, Colle Isabelle, Morales-Ruiz Manuel, Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice, 10.1002/hep.24238
  31. Zhan Lei, Huang Cheng, Meng Xiao-Ming, Song Yang, Wu Xiao Qin, Yang Yang, Li Jun, Hypoxia-inducible factor-1alpha in hepatic fibrosis: A promising therapeutic target, 10.1016/j.biochi.2014.10.013
  32. Li Xiaohui, Wang Yarui, Wang Huan, Huang Cheng, Huang Yan, Li Jun, Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis, 10.1007/s00011-014-0772-y
  33. Pereira Ethel R., Liao Nan, Neale Geoff A., Hendershot Linda M., Transcriptional and Post-Transcriptional Regulation of Proangiogenic Factors by the Unfolded Protein Response, 10.1371/journal.pone.0012521
  34. Autiero M., Luttun A., Tjwa M., Carmeliet P., Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders, 10.1046/j.1538-7836.2003.00263.x
  35. Snuderl Matija, Batista Ana, Kirkpatrick Nathaniel D., Ruiz de Almodovar Carmen, Riedemann Lars, Walsh Elisa C., Anolik Rachel, Huang Yuhui, Martin John D., Kamoun Walid, Knevels Ellen, Schmidt Thomas, Farrar Christian T., Vakoc Benjamin J., Mohan Nishant, Chung Euiheon, Roberge Sylvie, Peterson Teresa, Bais Carlos, Zhelyazkova Boryana H., Yip Stephen, Hasselblatt Martin, Rossig Claudia, Niemeyer Elisabeth, Ferrara Napoleone, Klagsbrun Michael, Duda Dan G., Fukumura Dai, Xu Lei, Carmeliet Peter, Jain Rakesh K., Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma, 10.1016/j.cell.2013.01.036
  36. Fels Diane R., Koumenis Constantinos, The PERK/eIF2α/ATF4 module of the UPR in hypoxia resistance and tumor growth, 10.4161/cbt.5.7.2967
Bibliographic reference Vandewynckel, Yves-Paul ; Laukens, Debby ; Devisscher, Lindsey ; Bogaerts, Eliene ; Paridaens, Annelies ; et. al. Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma.. In: BMC Cancer, Vol. 16, no.1, p. 9 [1-10] (2016)
Permanent URL http://hdl.handle.net/2078.1/186923