PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma

Nature Communications
Tianrun LiuYi Fan

Abstract

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls anti-angiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer.

References

Aug 12, 1971·The New England Journal of Medicine·J Folkman
Sep 15, 1999·Nature·J A Romashkova, S S Makarov
Oct 3, 1999·Physiological Reviews·C H Heldin, B Westermark
May 8, 2002·Nature Reviews. Molecular Cell Biology·M Angela Nieto
Aug 22, 2002·Nature Reviews. Cancer·Jean Paul Thiery
Jun 5, 2003·Nature Medicine·Napoleone FerraraJennifer LeCouter
Mar 11, 2005·The New England Journal of Medicine·Roger StuppUNKNOWN National Cancer Institute of Canada Clinical Trials Group
Apr 25, 2006·Nature Reviews. Molecular Cell Biology·Anna-Karin OlssonLena Claesson-Welsh
Jan 16, 2007·Cancer Cell·Christopher CalabreseRichard J Gilbertson
May 18, 2007·Nature Reviews. Cancer·Héctor PeinadoAmparo Cano
May 17, 2008·Genes & Development·Johanna AndraeChrister Betsholtz
Jul 25, 2008·Nature Reviews. Cancer·Gabriele Bergers, Douglas Hanahan
Sep 18, 2008·British Journal of Cancer·S PotentaR Kalluri
Dec 3, 2008·Archives of Biochemistry and Biophysics·Dayami LopezW Bradford Carter
Jun 3, 2009·The Journal of Clinical Investigation·Raghu Kalluri, Robert A Weinberg
Sep 2, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Henry S FriedmanTimothy Cloughesy
Nov 26, 2010·Nature·Rong WangViviane Tabar
Dec 22, 2010·Proceedings of the National Academy of Sciences of the United States of America·Christoph H ÖsterreicherDavid A Brenner
Jan 26, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yasushi SodaInder M Verma
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
May 20, 2011·Nature·Peter Carmeliet, Rakesh K Jain
Jun 2, 2011·Nature Reviews. Drug Discovery·Peter Carmeliet, Rakesh K Jain
Aug 17, 2011·Cancer Research·Daniel CiznadijaAndrew Koff
Nov 9, 2011·Nature Medicine·Sara M Weis, David A Cheresh
Sep 14, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Steve ScullyRong Shao
Jan 2, 2013·Frontiers in Bioscience (Landmark Edition)·Johanna DonovanJill Norman
Jun 4, 2013·Nature Cell Biology·Cyrus M GhajarMina J Bissell
Feb 21, 2014·The New England Journal of Medicine·Mark R GilbertMinesh P Mehta
Feb 21, 2014·The New England Journal of Medicine·Olivier L ChinotTimothy Cloughesy
Feb 22, 2014·Nature Reviews. Molecular Cell Biology·Samy LamouilleRik Derynck

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Citations

May 30, 2020·Experimental & Molecular Medicine·Kyu Jin ChoiYoon-Jin Lee
Sep 22, 2019·Cells·József Jászai, Mirko H H Schmidt
Apr 16, 2020·Cancers·Vilashini RajaratnamShama Parveen Mirza
Sep 15, 2020·Frontiers in Cell and Developmental Biology·Nicolas ClereIsabelle Corre
Oct 28, 2019·Journal of Biomedical Science·Tien HsuMaria Trojanowska
Mar 29, 2020·Signal Transduction and Targeted Therapy·Yuan-Hong XieJing-Yuan Fang
Apr 8, 2020·Journal of Experimental & Clinical Cancer Research : CR·Jianye XuGang Li
Jan 16, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Anna M Krichevsky, Erik J Uhlmann
Aug 11, 2020·Frontiers in Cell and Developmental Biology·Christopher Montemagno, Gilles Pagès
Jun 27, 2019·Proceedings of the National Academy of Sciences of the United States of America·Zhihong ChenDolores Hambardzumyan
Apr 1, 2020·Frontiers in Genetics·Nathan WeinsteinElena R Álvarez-Buylla
Oct 11, 2020·International Journal of Molecular Sciences·Maria PeleliAndreas Papapetropoulos
Nov 4, 2020·Brain : a Journal of Neurology·Antonio C Fuentes-FayosRaúl M Luque
Nov 17, 2020·Journal of the American Heart Association·Laura E BruijnJan H N Lindeman
Oct 13, 2019·Cancer Letters·Silvia MatteoniMarco G Paggi
Apr 17, 2020·Signal Transduction and Targeted Therapy·Yuan-Hong XieJing-Yuan Fang
Mar 19, 2021·Bone Research·Yan HuJiacan Su
Mar 26, 2021·Acta Neuropathologica Communications·Yona KimSun Ha Paek
Apr 4, 2021·Cancers·Meet PatelNeelu Puri
May 1, 2021·International Journal of Molecular Sciences·Filipa Lopes-CoelhoJacinta Serpa
Jun 8, 2021·Frontiers in Cell and Developmental Biology·Yanghong NiXuelei Ma
Jul 3, 2021·International Journal of Molecular Sciences·Sara Rosińska, Julie Gavard
Jul 11, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhaohui HeMao Luo
Aug 6, 2021·Drug Delivery and Translational Research·Seung Woo ChungJung Soo Suk

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Datasets Mentioned

BETA
AB5320
GSE115850

Methods Mentioned

BETA
flow cytometry
transgenic
RNA-seq
ChIP
PCR
mechanical dissociation
chips
electrophoresis

Software Mentioned

Cufflinks
RNA
Endo
MT
Star
Prism

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