Close

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Amber N Stratman, Olivia M Farrelly, Constantinos M Mikelis, Mayumi F Miller, Zhiyong Wang, Van N Pham, Andrew E Davis, Margaret C Burns, Sofia A Pezoa, Daniel Castranova, Tina M Kilts, George E Davis, J. Silvio Gutkind, Weijun Pan, Brant M Weinstein

Preprint posted on August 28, 2018 https://www.biorxiv.org/content/early/2018/08/28/402362

Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-020-14956-z

When not recycling cleans a mess; halting tumor-associated vascular overgrowth by blocking lipid recycling

Selected by Coert Margadant

When not recycling cleans a mess; halting tumor-associated vascular overgrowth by blocking lipid recycling

 

Background

The formation of new blood vessels through sprouting angiogenesis is essential for many physiological processes, but excessive angiogenesis is a hallmark of cancer. Vascular endothelial growth factor (VEGF) signaling through the receptor tyrosine kinase VEGFR2 is a key player in sprouting angiogenesis, but strategies to combat cancer by targeting the VEGF-VEGFR2 system have largely failed because tumor cells can overcome such inhibition, for example by excess production of VEGF and other pro-angiogenic cytokines. VEGF-VEGFR2 interaction activates a number of signaling events in endothelial cells, including the generation of phosphoinositide lipid secondary messengers by phosphoinositide 3-kinase and phospholipase C-gamma (PLCγ), which both use phosphatidylinositol-(4,5)-bisphosphate (PIP2) as a substrate. PLCγ converts PIP2 to IP3 and diacylglycerol (DAG). The latter is ‘recycled’ to Cytidine-Diphosphate (CDP)-DAG by CDP-Diacylglycerol Synthases or CDS enzymes, which leads to replenishment of PIP2. A previous publication from the Weinstein lab had shown that this CDS enzyme-dependent phospholipid recycling loop is required for VEGF-induced angiogenesis, because loss or knockdown of CDS enzymes reduces angiogenesis, and this can be rescued by experimental elevation of PIP2 levels (1).

 

Key findings

In this preprint, the authors further explore the role of PIP2 recycling in VEGF signaling and angiogenesis. Strikingly, they find in human endothelial cells in vitro and zebrafish embryos that VEGF treatment does not counteract the angiogenic defects induced by loss of CDS enzymes, but in fact exacerbates them. The VEGF effect is dose-dependent and can be rescued by PIP2 administration, suggesting that in the absence of PIP2 recycling, high VEGF concentrations deplete PIP2 levels faster and more strongly, thereby ‘exhausting’ the pool of PIP2 and halting VEGF signaling. Thus, inhibition of PIP2 recycling can actually switch VEGF from a pro-angiogenic to an anti-angiogenic stimulus.

So, does this also work in tumors? To answer this question the authors employed a number of different approaches including intravascular administration of either morpholinos against CDS2, or pharmacological agents that block phosphoinositide recycling, in two different murine tumor allograft models (melanoma and lung carcinoma). All of these treatments reduced tumor growth, which was not due to direct effects on the tumor cells, and lead to a strongly diminished vascular density. Importantly, the reduction in angiogenesis could be reversed by co-administration of PIP2 liposomes. In addition to the mentioned strategies, which systemically inhibit PIP2 recycling, the authors made similar observations in an inducible endothelial-specific CDS2 knockout mouse model. Thus, inhibition of PIP2 recycling blocks growth and expansion of tumor-associated vessels, but interestingly without effects on the endogenous vasculature. Tumor vessels are likely more prone to this treatment because they are hyperactivated and consume (and recycle) much more PIP2 than normal vessels, which are mainly quiescent. Therefore, these findings open up the intriguing possibility that blockade of phosphoinositide recycling may improve anti-angiogenic treatment in tumors.

 

What I like

This paper shows how a ‘classic’ pro-angiogenic signal such as VEGF can be turned into an anti-angiogenic signal by changing the balance between consumption and recycling of essential downstream mediators. Since side-effects on the normal vasculature seem minimal, probably because quiescent vessels do not consume such excess amounts of phosphoinositides, the results may guide new options to target tumor angiogenesis. Importantly, overproduction of VEGF in the tumor micro-environment will in this scenario not overcome the treatment, but may in fact enhance its effectiveness.

 

Future directions

Obviously, it remains to be determined how the data presented here will translate to human patients. Will vessels in different tumors respond differently? Will only vessels in VEGF-overproducing tumors be sensitive to a block in PIP2 recycling? Does the sensitivity depend on the presence of other cytokines and growth factors? While further studies will be required, the current work provides an exciting novel concept in anti-angiogenic treatment.

 

References

 

1 Pan W, et al. (2012) CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis. Blood 120:489-98

 

 

 

 

Posted on: 6th September 2018

doi: https://doi.org/10.1242/prelights.4693

Read preprint (2 votes)




Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the cell biology category:

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage

Also in the developmental biology category:

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

Society for Developmental Biology 79th Annual Meeting

Preprints at SDB 2020

 



List by Irepan Salvador-Martinez, Martin Estermann

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EDBC Alicante 2019

Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.

 



List by Sergio Menchero et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve

Pattern formation during development

The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.

 



List by Alexa Sadier

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

 



List by Shikha Nayar
Close