Tumor vessel co-option probed by single-cell analysis

Teuwen, Laure-Anne; Rooij, Laura P.M.H. de; Cuypers, Anne; Rohlenová, Kateřina; Dumas, Sébastien J.; García-Caballero, Melissa; Meta, Elda; Amersfoort, J.M.M. van; Taverna, Federico; Becker, Lisa; Veiga, Nuphar; Cantelmo, Anna Rita; Geldhof, Vincent; Conchinha, Nadine V.; Kalucka, Joanna; Treps, Lucas; Conradi, Lena‐Christin; Khan, Shawez; Karakach, Tobias K.; Soenen, Stefaan; Vinckier, Stefan; Schoonjans, Luc; Eelen, Guy; Laere, Steven Van; Dewerchin, Mieke; Dirix, Luc; Mazzone, Massimiliano; Luo, Yonglun; Vermeulen, Peter; Carmeliet, Peter

doi:10.1016/j.celrep.2021.109253

Cited by 60 publications

(86 citation statements)

References 156 publications

(213 reference statements)

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“…As widely discussed across this review, LRG1 orchestrates pathological blood vessel formation [ 29 ] by enhancing proliferation, migration and invasion of endothelial cells [ 35 ], as well as the expression of several pro-angiogenic factors including TGFβ, VEGFA and Angiopoietin-1, in both endothelial [ 35 , 190 ] and cancer cells [ 197 ]. A recent study on tumour vessel co-option, where tumours grow around existing vessels rather than through neoangiogenesis, revealed that Lrg1 was one of the few genes significantly upregulated in endothelial cells, as both endothelial and pericyte transcriptomes were otherwise largely indistinguishable from those of normal vessels [ 201 ]. The effects of LRG1 on the cancer vasculature are therefore most likely inevitable and supportive of tumour progression.…”

Section: Reviewmentioning

confidence: 99%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

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Section: Reviewmentioning

confidence: 99%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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“…Neutrophils have been recently shown to contribute to tumor vascularization, also through non-angiogenic mechanisms, vessel co-option, and vascular mimicry [106,107]. High neutrophil expression of LOXL4 in colorectal cancer liver metastases (mainly via vessel co-option) has been proposed to be the key factor responsible for the resistance against antiangiogenic therapy [108].…”

Section: Neutrophils and Tumor Angiogenesismentioning

confidence: 99%

The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer

Ozel

Duerig

Domnich

et al. 2022

Cancers

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Angiogenesis, the formation of new blood vessels from already existing vasculature, is tightly regulated by pro- and anti-angiogenic stimuli and occurs under both physiological and pathological conditions. Tumor angiogenesis is central for tumor development, and an “angiogenic switch” could be initiated by multiple immune cells, such as neutrophils. Tumor-associated neutrophils promote tumor angiogenesis by the release of both conventional and non-conventional pro-angiogenic factors. Therefore, neutrophil-mediated tumor angiogenesis should be taken into consideration in the design of novel anti-cancer therapy. This review recapitulates the complex role of neutrophils in tumor angiogenesis and summarizes neutrophil-derived pro-angiogenic factors and mechanisms regulating angiogenic activity of tumor-associated neutrophils. Moreover, it provides up-to-date information about neutrophil-targeting therapy, complementary to anti-angiogenic treatment.

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“…Some other evidence suggests that tumour cells can compress and destabilise the pre-existing vasculature, activating a host defence mechanism which initiates an apoptotic response leading to regression of co-opted vessels and perfusion impairment [83]. This ultimately leads to hypoxia and necrosis triggering further neovascularisation, so a combination of neovascularisation and co-option can exist together [84].…”

Section: Vessel Co-optionmentioning

confidence: 99%

“…Vessel co-option has been suggested as a mechanism of resistance to anti-angiogenic therapy [83]. Preclinical models of pulmonary metastases display vessel co-option after anti-VEGF therapy [84]. On the other hand, it was shown that in human patients with colorectal cancer liver metastasis, vessel co-option appears in those with poor response to the anti-angiogenic drug bevacizumab [85].…”

Section: Vessel Co-optionmentioning

confidence: 99%

Improved Immunotherapy Efficacy by Vascular Modulation

Newport

Pedrosa

Njegic

et al. 2021

Cancers

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Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development of immunotherapies has led to significant improvements in cancer treatment. Particularly promising are immune checkpoint blockade and CAR T cell therapies, which use antibodies against negative regulators of T cell activation and T cells reprogrammed to better target tumour antigens, respectively. However, while immunotherapy is successful in some patients, including those with advanced or metastatic cancers, only a subset of patients respond. Therefore, better predictors of patient response and methods to overcome resistance warrant investigation. Poor, or periphery-limited, T cell infiltration in the tumour is associated with poor responses to immunotherapy. Given that (1) lymphocyte recruitment requires leucocyte–endothelial cell adhesion and (2) the vasculature controls tumour oxygenation and plays a pivotal role in T cell infiltration and activation, vessel targeting strategies including anti-angiogenesis and vascular normalisation in combination with immunotherapy are providing possible new strategies to enhance therapy. Here, we review the progress of vessel modulation in enhancing immunotherapy efficacy.

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Tumor vessel co-option probed by single-cell analysis

Cited by 60 publications

References 156 publications

LRG1: an emerging player in disease pathogenesis

LRG1: an emerging player in disease pathogenesis

The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer

Improved Immunotherapy Efficacy by Vascular Modulation

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