LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

O’Connor, Marie; Kallenberg, David; Camilli, Carlotta; Pilotti, Camilla; Dritsoula, Athina; Jackstadt, René; Bowers, Chantelle E.; Watson, H. Angharad; Alatsatianos, Markella; Ohme, Julia; Dowsett, Laura; George, Jestin; Blackburn, Jack W. D.; Singhal, Mahak; Augustin, Hellmut G.; Ager, Ann; Sansom, Owen J.; Moss, Stephen E.; Greenwood, John

doi:10.1016/j.medj.2021.10.002

Cited by 27 publications

(41 citation statements)

References 86 publications

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“…Having established that LRG1 corrupts the angiogenic process, we next investigated whether IL-6 is implicated in LRG1-driven pathogenic angiogenesis by assessing its effect on LRG1 gene expression. Our previous work has shown that in neovascular complications of the retina, Lrg1 expression is restricted to the neovascular endothelial cells 15 , 44 , and in LRG1-negative tumours its expression is restricted to the tumour neovascular endothelial cells 19 . Consistent with these previous data, low levels of Lrg1 gene expression were observed in cultured mouse brain microvascular endothelial cells (MBMEC), while the Lrg1 transcript was not detectable in pericytes from the same source (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 98%

“…1 b), as previously reported 15 . Since LRG1 exhibits angiopathic properties and may interfere with the delicate interplay between the endothelium and mural cells 19 , we next investigated whether LRG1 altered this association. Angiogenic explant cultures were treated with exogenous LRG1, which resulted in a significant reduction in αSMA + and NG2 + mural cell coverage of vessels in the metatarsal bone assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Associated with disturbances in these signalling pathways is disruption of the close spatial proximity between pericytes and endothelial cells and this is most evident in the tumour environment 24 . In this context, we have shown that LRG1 is a causal factor in disrupting the endothelial-mural cell association in various tumour models and that antibody blockade or genetic deletion of Lrg1 results in improved mural cell coverage and vascular function 19 . Consistent with this, tumour vessels exhibited reduced vascular leakage, increased perfusion, and enhanced chemotherapeutic and immunotherapeutic efficacy 19 .…”

Section: Introductionmentioning

confidence: 97%

“…In this context, we have shown that LRG1 is a causal factor in disrupting the endothelial-mural cell association in various tumour models and that antibody blockade or genetic deletion of Lrg1 results in improved mural cell coverage and vascular function 19 . Consistent with this, tumour vessels exhibited reduced vascular leakage, increased perfusion, and enhanced chemotherapeutic and immunotherapeutic efficacy 19 . This evidence collectively establishes LRG1 as an important vascular destabilising factor and illustrates its potential as a therapeutic target that may be of significant relevance to diseases where vascular dysfunction is problematic.…”

Section: Introductionmentioning

confidence: 97%

“…This is currently most evident in the eye and kidney, where it plays a central role in the vascular dysfunction observed in models of retinal neovascularisation and diabetic kidney disease and is consistent with raised LRG1 levels in patients with these diseases 15 – 17 . Moreover, in cancer, where there is an emerging body of evidence for a pathogenic role for LRG1 14 , 18 , the induction of LRG1 in tumour endothelial cells has also been shown to contribute to pathological neovascularisation 19 and priming the vascular metastatic niche 20 establishing this secreted glycoprotein as a new vasculopathic molecule.…”

Section: Introductionmentioning

confidence: 99%

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Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Dritsoula

Dowsett

Pilotti

et al. 2022

Sci Rep

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Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Dritsoula

Dowsett

Pilotti

et al. 2022

Sci Rep

Self Cite

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ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3‐Dependent Manner

Zhu,

Guo,

Liu

et al. 2023

Advanced Science

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Although the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of MAPK, ELK4 is thought to work primarily by forming a complex with SRF. Whether ELK4 can serve as a potential therapeutic target is unclear and the transcriptional regulatory mechanism has not been systemically analyzed. Here, it is shown that ELK4 promotes CRC tumorigenesis. Integrated genomics‐ and proteomics‐based approaches identified SP1 and SP3, instead of SRF, as cooperative functional partners of ELK4 at genome‐wide level in CRC. Serum‐induced phosphorylation of ELK4 by MAPKs facilitated its interaction with SP1/SP3. The pathological neoangiogenic factor LRG1 is identified as a direct target of the ELK4‐SP1/SP3 complex. Furthermore, targeting the ELK4‐SP1/SP3 complex by combination treatment with MEK/ERK inhibitor and the relatively specific SP1 inhibitor mithramycin A (MMA) elicited a synergistic antitumor effect on CRC. Clinically, ELK4 is a marker of poor prognosis in CRC. A 9‐gene prognostic model based on the ELK4‐SP1/3 complex‐regulated gene set showed robust prognostic accuracy. The results demonstrate that ELK4 cooperates with SP1 and SP3 to transcriptionally regulate LRG1 to promote CRC tumorigenesis in an SRF‐independent manner, identifying the ELK4‐SP1/SP3 complex as a potential target for rational combination therapy.

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Targets of tumor microenvironment for potential drug development

Zhang,

Wang,

Liu

et al. 2024

MedComm – Oncology

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The tumor microenvironment (TME) is the ecosystem surrounding a tumor, which usually consists of nontumoral cells or components, and molecules they produce and release. The frequent and continuous interplay between tumor cells and the TME strongly affects tumor development, disease progression, metastasis, and responses to therapeutic interventions. As a hub of potential therapeutic targets, the TME has gained appreciable momentum in cancer research. Here we systematically review the progress in targeting the TME as a strategy to develop novel antitumor drugs from the immunological, stromal and extracellular matrix components of the TME, shedding light on its complex synergies with tumor cells. This exploration highlights the transformative potential these elements hold in refining cancer treatment approaches. This thorough examination not only accentuates the TME's multifaceted nature but also positions it as a formidable avenue for propelling forward the paradigms of cancer therapy. This review aims to foster a deeper understanding of the TME's role in oncogenesis and its potential exploitation in advancing targeted, efficacious cancer treatments, marking a significant stride in the realm of cancer research.

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LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

Cited by 27 publications

References 86 publications

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3‐Dependent Manner

Targets of tumor microenvironment for potential drug development

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