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TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer
Activation of the cGAS-STING pathway has been associated with the promotion of anti-tumor immunity. Here the authors show that TET2 upregulates tumor cGAS to activate STING in endothelial cells, inducing tumor vascular normalization and enhancing efficacy of anti-PD-L1 alone or combined with IL-2 in liver cancer preclinical models.
- Hongwei Lv
- , Qianni Zong
- & Wen Yang
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Article
| Open Access
Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis
Chaube et al. show that ANGPTL4 is an important player for endothelial cell metabolic function, impacting vascular permeability and angiogenesis. Knocking down ANGPTL4 increases fatty acid utilization but impairs glucose use, reducing neovascularization
- Balkrishna Chaube
- , Kathryn M. Citrin
- & Yajaira Suárez
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Article
| Open Access
Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial
Combination of immune checkpoint inhibitors with anti-angiogenic targeted therapy has shown efficacy in some solid tumours. Here the authors report the results of a phase 2 trial of camrelizumab (anti-PD1) plus apatinib as a second-line or later-line treatment regimen in platinum-resistant (cohort 1) or PD-1 inhibitor-resistant (cohort 2) Recurrent/Metastatic Nasopharyngeal Carcinoma patients.
- Li Yuan
- , Guo-Dong Jia
- & Hai-Qiang Mai
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Article
| Open Access
ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma
The mechanisms of angiogenesis in alveolar soft part sarcoma (ASPS) remain to be explored. Here, the authors highlight the role of the ASPSCR1::TFE3 fusion in regulating super-enhancer activity during the angiogenic process in ASPS.
- Miwa Tanaka
- , Surachada Chuaychob
- & Takuro Nakamura
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| Open Access
Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses
The immune suppressive tumour microenvironment drives recurrence and metastatic disease in prostate cancer. Here authors provide a detailed analysis of the microenvironment via single cell RNA sequencing and high-resolution spatial transcriptomics to identify tumour-dependent changes compared to healthy tissue.
- Taghreed Hirz
- , Shenglin Mei
- & David B. Sykes
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Article
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Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells
Glioma stem-like cells (GSCs) exhibit plasticity during proneural-to-mesenchymal transition. Here the authors show that extracellular vesicles from endothelial cells can promote this transition of GSCs through activation of MMPs and NFkB, and inactivation of NOTCH.
- Lata Adnani
- , Jordan Kassouf
- & Janusz Rak
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| Open Access
In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
- Aditi Sahu
- , Kivanc Kose
- & Milind Rajadhyaksha
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Article
| Open Access
Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis
Tumour-associated angiogenesis facilitates the growth of tumours. Here the authors show that integrin α3β1 promotes blood vessel formation in glioblastoma through calcium-mediated macropinocytosis and lysosomal exocytosis.
- Eunnyung Bae
- , Ping Huang
- & Candece L. Gladson
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Article
| Open Access
Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy
The pro-tumorigenic effects of vimentin have been attributed to intracellular functions in tumour cells so far. Here, the authors show that tumour endothelial cells can secrete vimentin as a pro-angiogenic factor and that targeting of vimentin can be used as an immunotherapeutic strategy.
- Judy R. van Beijnum
- , Elisabeth J. M. Huijbers
- & Arjan W. Griffioen
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Article
| Open Access
Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer
The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.
- Meng Wang
- , Yue Li
- & Libing Song
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Article
| Open Access
Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization
SHP2 regulates pro-angiogenic VEGF-VEGFR signalling, but its role in tumour angiogenesis is unclear. Here the authors show that endothelial cell-specific deletion of SHP2 impairs tumour growth and angiogenesis in syngeneic mouse models through ASK1-c-JunSOX7 signalling axis.
- Zhiyong Xu
- , Chunyi Guo
- & Hongqiang Cheng
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Article
| Open Access
A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis
UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.
- Davide Pradella
- , Gianluca Deflorian
- & Claudia Ghigna
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Article
| Open Access
Refractoriness of STING therapy is relieved by AKT inhibitor through effective vascular disruption in tumour
How STING agonists exert anti-tumour effects remains unclear. Here, the authors show that STING agonists suppress tumor growth of subcutaneous xenografts models inducing early apoptosis of endothelial cells through the TNFalpha-TNFR1 signaling, while in primary tumors, additional inhibition of AKT is required for efficient induction of apoptosis via the same pathway.
- Seung-hwan Jeong
- , Myung Jin Yang
- & Gou Young Koh
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Article
| Open Access
FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis
Mitochondria-associated ER membranes (MAMs) are involved in the regulation of many cellular functions. Here, the authors report that FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes play an essential role in the process of angiogenesis and neoangiogenesis.
- Cheng Wang
- , Xiaoyan Dai
- & Kai Huang
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Article
| Open Access
Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis
Slug supports heart development and tumor metastasis, but its role in blood vessel formation is less clear. Here the authors show that endothelial cell-expressed Slug regulates both physiologic and pathological angiogenesis, at least in part through the modulation of Notch signalling.
- Nan W. Hultgren
- , Jennifer S. Fang
- & Christopher C. W. Hughes
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| Open Access
Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors
Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.
- Kayoko Hosaka
- , Yunlong Yang
- & Yihai Cao
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Article
| Open Access
Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth
During angiogenesis the vasculature switches from a quiescent to a proliferative state. Here the authors show that mitochondrial respiration in endothelial cells controls angiogenesis during development, tumour growth and tissue repair.
- L. M. Schiffmann
- , J. P. Werthenbach
- & H. Kashkar
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Article
| Open Access
Cancer associated fibroblast FAK regulates malignant cell metabolism
Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.
- Fevzi Demircioglu
- , Jun Wang
- & Kairbaan Hodivala-Dilke
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Article
| Open Access
Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
Tumors can overproduce pro-angiogenic ligands overcoming currently approved anti-angiogenic therapies and hindering their success. Here, the authors show that targeting phosphoinositide recycling during tumor angiogenesis harnesses the tumor’s own production of angiogenic ligands to deplete adjacent endothelial cells of the capacity to respond to these signals.
- Amber N. Stratman
- , Olivia M. Farrelly
- & Brant M. Weinstein
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| Open Access
Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling
Mesenchymal cells contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. Here, the authors show that mesenchymal stem cells also have the ability to acquire an endothelial phenotype upon TGF-β stimulation via the downstream kinase JNK, and that p38α negatively regulates this process.
- Raquel Batlle
- , Eva Andrés
- & Angel R. Nebreda
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Article
| Open Access
Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer
Bladder cancer is one of the most common and highly vascularized cancers. Here the authors perform a whole-genome analysis in urothelial bladder carcinomas and identify recurrent genetic alterations in a set of angiogenesis genes, facilitating the understanding of molecular mechanisms underlying pathological angiogenesis in this type of cancer.
- Song Wu
- , Tong Ou
- & Zhiming Cai
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Article
| Open Access
A miniature multi-contrast microscope for functional imaging in freely behaving animals
Measuring multiple neurophysiologic variables usually requires bulky benchtop optical systems and working with anesthetized animals. Here the authors present a miniature portable microscope for neurovascular imaging in awake rodents, combining fluorescence, intrinsic optical signals and laser speckle contrast.
- Janaka Senarathna
- , Hang Yu
- & Arvind P. Pathak
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| Open Access
Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis
The contribution of endothelial progenitor cells to tumor angiogenesis is controversial. Here, the authors trace the lineage differentiation of endovascular progenitor cells and demonstrate their functional importance in tumor vascularization and progression.
- Prudence Donovan
- , Jatin Patel
- & Kiarash Khosrotehrani
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Article
| Open Access
Vasculogenic mimicry formation in EBV-associated epithelial malignancies
EBV latent infection contributes to the pathogenesis of epithelial malignancies by inducing angiogenesis. Here, the authors show EBV promotes vasculogenic mimicry in EBV associated epithelial cancers via AKT/HIF-1α pathway and combination therapy of HIF-1α and VEGF reduces tumour growth.
- Tong Xiang
- , Yu-Xin Lin
- & Lin Feng
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Article
| Open Access
Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer
Identification of response biomarkers is a key step towards the development of personalised care. Here, Jayson et al. identify plasma Tie2 as a biomarker for the response of the tumor vasculature to anti-angiogenics in patients with metastatic colorectal cancer, suggesting that monitoring Tie2 levels may help guide therapy in the clinics.
- Gordon C. Jayson
- , Cong Zhou
- & Caroline Dive
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Article
| Open Access
Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy
Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and bevacizumab treatment, suggesting CIN as a predictive biomarker.
- Dominiek Smeets
- , Ian S. Miller
- & Annette T. Byrne
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Article
| Open Access
PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma
Resistance to anti-angiogenic therapies often occurs in patients. Here, the authors demonstrate the role of PDGF signaling in GBM resistance to anti-VEGF treatment via a mechanism that involves endothelial-mesenchymal transformation and transcriptional regulation of VEGFR-2.
- Tianrun Liu
- , Wenjuan Ma
- & Yi Fan
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Article
| Open Access
Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface
A soluble form E-cadherin is highly expressed in ovarian cancer. Here, the authors show that soluble E-cadherin is released by ovarian cancer cells packaged in exosomes and promotes tumor angiogenesis through β-catenin and NFkB signaling activation.
- Maggie K. S. Tang
- , Patrick Y. K. Yue
- & Alice S. T. Wong
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Article
| Open Access
SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α
Tumour vasculature influences drug delivery. Here, the authors show that SOD3 re-expression enhances doxorubicin delivery and effects through normalization of tumour vasculature via the HIF-2a/VE-cadherin pathway.
- Emilia Mira
- , Lorena Carmona-Rodríguez
- & Santos Mañes
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| Open Access
3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry
Extracellular matrix plays a central role in driving cancer development. Here the authors using an in vitro approach show that confining collagen architectures induce fast and persistent cell migration and the formation of multicellular network structures linked to vascular mimicry observed in tumours from patients.
- D. O. Velez
- , B. Tsui
- & S. I. Fraley
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Article
| Open Access
Loss of HIF-1α in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis
Tumour hypoxia influences both the immune responses and angiogenesis. Here, the authors show that HIF-1α deletion in NK cells impairs NK cytotoxic activity but inhibit tumour growth by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1, thus resulting in non-functional angiogenesis.
- Ewelina Krzywinska
- , Chahrazade Kantari-Mimoun
- & Christian Stockmann
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Article
| Open Access
Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma
The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
- Qingbo Huang
- , Yin Sun
- & Chawnshang Chang
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| Open Access
Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity
Angiogenesis is essential for solid tumor progression. Here, the authors interrogate the proteome of pancreatic cancer endothelium via phage display and identify hornerin as a critical protein whose expression is essential to maintain the pancreatic cancer vasculature through a VEGF-independent mechanism.
- Michael F. Gutknecht
- , Marc E. Seaman
- & Kimberly A. Kelly
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| Open Access
Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B
Resistance towards VEGF-centered anti-angiogenic therapy is an important clinical challenge. Here, the authors show that mast cells mediate resistance to anti-angiogenetic inhibitors by altering the proliferative and organizational state of endothelial cells through mobilization of FGF-1 and GM-CSF from the tumor matrix and secretion of FGF-2.
- M. Wroblewski
- , R. Bauer
- & S. Loges
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Article
| Open Access
Pericyte-expressed Tie2 controls angiogenesis and vessel maturation
The angiopoietins regulate vascular maturation, angiogenesis and lymphangiogenesis via their Tie receptors that were long believed to be endothelium-specific. Here the authors show that angiopoietins activate and control pericyte function through pericyte-expressed Tie2 triggering of Calpain, Akt and FOXO3A signalling cascades.
- Martin Teichert
- , Laura Milde
- & Hellmut G. Augustin
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Article
| Open Access
Non-canonical NOTCH3 signalling limits tumour angiogenesis
Notch signalling is deregulated in several cancers; therefore, strategies targeting this pathway are currently being explored. Here the authors report a pro-apoptotic function of Notch3 in endothelial cells; consequently, when Notch3 is silenced in stroma cells, tumour growth and angiogenesis are increased.
- Shuheng Lin
- , Ana Negulescu
- & Patrick Mehlen
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Article
| Open Access
Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression
Cancer cells can affect cancer progression by producing systemic effects. Here, the authors show that IGF2 produced by oesophageal cancer cells increases secretion of VEGF from cancer-associated fibroblasts resulting in systemic mobilization of bone marrow-derived cells and increased metastases.
- Wen Wen Xu
- , Bin Li
- & Annie L. M. Cheung
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Article
| Open Access
MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment
The tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here the authors show that radiation induced miR-103 downregulates TREX1 in endothelial cells, decreases angiogenesis and leads to the secretion of proinflammatory mediators that reduce tumour growth.
- RaeAnna Wilson
- , Cristina Espinosa-Diez
- & Sudarshan Anand
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Article
| Open Access
Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism
Anti-VEGF therapy often produces limited beneficial effects in cancer patients. Here, the authors show that discontinuation of anti-VEGF cancer therapy in xenografts-bearing mice increases cancer cells extravasation and intravasation in liver through the host-derived VEGF.
- Yunlong Yang
- , Yin Zhang
- & Yihai Cao
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Article
| Open Access
Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia
Chemerin is an adipokine often downregulated in tumours. Here the authors show that chemotherapy induces chemerin production by endothelial cells, leading to cachexia, and that VEGF ablation in myeloid cells prevents cachexia in a chemerin-dependent manner, and improves chemotherapeutic effects.
- Ralph Klose
- , Ewelina Krzywinska
- & Christian Stockmann
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Article
| Open Access
A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer
The formation of blood vessels in tumours, angiogenesis, is a promising target for therapy. Here, the authors show that microRNA192 has anti-angiogenic functions and negatively regulates EGR1 and HOXB9, and that delivery of this microRNA to tumours in vivocan reduce angiogenesis and tumour growth.
- Sherry Y. Wu
- , Rajesha Rupaimoole
- & Anil K. Sood
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Article
| Open Access
Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis
HIF-1α is a pivotal protein involved in angiogenesis and is known to be regulated posttranslationally. Here, the authors show that HIF-1α is methylated by Set7/9 methyltransferase, which reduces protein stability and contributes to reduced angiogenesis.
- Yunho Kim
- , Hye Jin Nam
- & Sung Hee Baek
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Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling
Targetting tumour angiogenesis is a useful strategy to reduce tumour burden; however, the clinical benefits of anti-angiogenetic drugs are modest. Here, the authors show that HGFR signalling, which contributes to tumour angiogenesis, requires Arf6 and that blocking Arf6 can lead to reduced tumour growth in mice.
- Tsunaki Hongu
- , Yuji Funakoshi
- & Yasunori Kanaho
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The Wilms’ tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression
The Wilms’ tumour suppressor Wt1 is highly expressed in vessels and stromal cells of human tumours, but not in adjacent healthy tissue. Here the authors show that Wt1 regulates Pecam-1 and c-kitand that deletion of Wt1 in endothelial, haematopoietic and myeloid suppressor cells leads to tumour regression.
- Kay-Dietrich Wagner
- , Julien Cherfils-Vicini
- & Nicole Wagner
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Vascular channels formed by subpopulations of PECAM1+ melanoma cells
Tumours acquire new vasculature through angiogenesis or through alternative pathways including the less understood vasculogenesis mimicry. Here the authors identify a vasculogenic mimicry-competent subpopulation of melanoma cells that expresses the vascular cell adhesion molecule PECAM1, but not VEGFR-2.
- James M. Dunleavey
- , Lin Xiao
- & Andrew C. Dudley
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TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
TNF-α signalling regulates a range of pathophysiological functions including tumour growth, but its role in lymphatic metastasis is unclear. Here the authors show that TNF-α signalling stimulates lymphatic endothelial cell activity, lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
- Hong Ji
- , Renhai Cao
- & Yihai Cao
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Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis
Tumour angiogenesis is critical for tumour growth and metastasis but the mechanisms that promote the growth of new blood vessels by tumours are not completely clear. Here the authors show that overexpression of the transcription factor Twist1 in certain tumour cells can lead them to differentiate into endothelial cells.
- Hsiao-Fan Chen
- , Chi-Hung Huang
- & Kou-Juey Wu
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Tumour angiogenesis regulation by the miR-200 family
The microRNA-200 family members have a role in regulating tumour angiogenesis but the underlying mechanism is unclear. In this study, Pecot et al.demonstrate that miR-200 affects angiogenesis by altering endothelial and cancer cell cytokine secretion.
- Chad V. Pecot
- , Rajesha Rupaimoole
- & Anil K. Sood
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FAK-heterozygous mice display enhanced tumour angiogenesis
Focal adhesion kinase (FAK) regulates angiogenesis and FAK inhibitors are currently developed as anticancer drugs. Here Kostourou and colleagues show that genetic FAK heterozygosity or low doses of a pharmacological FAK inhibitor unexpectedly increase angiogenesis and tumour growth in vitro and in vivo.
- Vassiliki Kostourou
- , Tanguy Lechertier
- & Kairbaan Hodivala-Dilke
Mesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR