Cancer Burden Is Controlled by Mural Cell-β3-Integrin Regulated Crosstalk with Tumor Cells

Wong, Ping-Pui; Muñoz‐Félix, José M.; Hijazi, Maruan; Kim, Hyojin; Robinson, Stephen D.; Luxán-Delgado, Beatriz de; Rodríguez-Hernández, Irene; Maiques, Óscar; Meng, Ya-Ming; Meng, Qiong; Bodrug, Natalia; Dukinfield, Matthew; Reynolds, Louise E.; Elia, George; Clear, Andrew; Harwood, Catherine A.; Wang, Yu; Campbell, James J.; Singh, Rajinder; Zhang, Penglie; Schall, Thomas J.; Matchett, Kylie P.; Henderson, Neil C.; Szlosarek, Peter W.; Dreger, Sally A.; Smith, Sally; Jones, J. Louise; Gribben, John G.; Cutillas, Pedro R.; Meier, Pascal; Sanz-Moreno, Victoria; Hodivala‐Dilke, Kairbaan

doi:10.1016/j.cell.2020.02.003

Cited by 63 publications

(56 citation statements)

References 76 publications

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“…Recently, Wong et al . showed how tumor growth also depends on novel integrin-dependent non-canonical function of pericytes that act as paracrine sources of tumor trophic factors 76 . Indeed, in different human cancers, the simple lack of β3 integrin in blood vessel mural cells correlates with a larger tumor size and clinically more aggressive phenotype 76 .…”

Section: Integrin In the Context Of Cancer Progression And Therapymentioning

confidence: 99%

“…showed how tumor growth also depends on novel integrin-dependent non-canonical function of pericytes that act as paracrine sources of tumor trophic factors 76 . Indeed, in different human cancers, the simple lack of β3 integrin in blood vessel mural cells correlates with a larger tumor size and clinically more aggressive phenotype 76 . Mechanistically, the absence of β3 integrin in pericytes, though not altering blood vessel number and function, upregulates the FAK-MET-AKT-NFKB–driven production of the cytokine CCL2 that in turn sustains tumor growth in a CCR2 receptor–dependent manner 76 .…”

Section: Integrin In the Context Of Cancer Progression And Therapymentioning

confidence: 99%

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The roles of integrins in cancer

Valdembri¹,

Serini²

2021

Fac Rev

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Integrin-mediated adhesion of cells to the extracellular matrix (ECM) is crucial for the physiological development and functioning of tissues but is pathologically disrupted in cancer. Indeed, abnormal regulation of integrin receptors and ECM ligands allows cancer cells to break down tissue borders, breach into blood and lymphatic vessels, and survive traveling in suspension through body fluids or residing in metabolically or pharmacologically hostile environments. Different molecular and cellular mechanisms responsible for the modulation of integrin adhesive function or mechanochemical signaling are altered and participate in cancer. Cancer development and progression are also bolstered by dysfunctionalities of integrin-mediated ECM adhesion occurring both in tumor cells and in elements of the surrounding tumor microenvironment, such as vascular cells, cancer-associated fibroblasts, and immune cells. Mounting evidence suggests that integrin inhibitors may be effectively exploited to overcome resistance to standard-of-care anti-cancer therapies.

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Section: Integrin In the Context Of Cancer Progression And Therapymentioning

confidence: 99%

Section: Integrin In the Context Of Cancer Progression And Therapymentioning

confidence: 99%

The roles of integrins in cancer

Valdembri¹,

Serini²

2021

Fac Rev

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“…Our data demonstrate that FAK-Y861F pericytes decrease tumour burden, at least in part, by directly affecting tumour cell apoptosis, and call for further consideration of the role of tumour pericytes in the direct control of tumour growth, in addition to their effects on vessel stabilisation. Indeed, we have recently shown that pericytes play a central role in the control of primary tumour growth, through cross-talk with multiple cell types in the tumour microenvironment [19,20]. FAK is upregulated in many cancer types and is currently being targeted as a potential anti-cancer agent because of its essential roles in tumour growth and angiogenesis [12,[32][33][34].…”

Section: Discussionmentioning

confidence: 99%

“…Whilst FAK has been studied extensively in endothelial cells, the function of FAK in pericytes during tumour growth and angiogenesis is starting to emerge, with loss of pericyte FAK enhancing tumour angiogenesis [19]. Given that pericytes are an important cell type in the regulation of tumour growth and paracrine signalling [20][21][22], here we have examined the role of FAK point mutations in pericytes during pathological angiogenesis. Specifically, we have examined the effect of non-phosphorylatable mutations of tyrosines 397 and 861 (Y397F and Y861F) -FAK residues using pericyte-specific FAK Y397F/Y397F and FAK Y861F/ Y861F mice.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

et al. 2021

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

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“…several disorders, from hypertension (Rodríguez-Vita et al, 2005a) and atherosclerosis (Rodríguez-Vita et al, 2008) to cancer (Wong et al, 2020) and more recently even COVID-19 (He et al, 2020). Whereas capillaries are mostly covered by pericytes, larger blood vessels contain VSCMs in the vessel wall.…”

mentioning

confidence: 99%

Isolation of Murine Primary Aortic Smooth Muscle Cells

Hubert¹,

Rodríguez-Vita²,

Wiedmann³

et al. 2021

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Vascular smooth muscle cells (VSMCs) have been cultured for decades to study the role of these cells in cardiovascular disorders. The most common source of VSMCs is the rat aorta. Here we show the adaptation of this method to isolate and culture mouse aortic VSMCs. The advantage of this method is that there are many more transgenic mouse lines available compared to rats. The protocol consists of the isolation of the aorta, the liberation of vascular cells by the action of collagenase, culturing of VSCMs, and analyzing filamentous actin and alpha smooth muscle actin by fluorescence microscopy. VSCMs can be further used to study mechanisms underlying cardiovascular diseases.

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Cancer Burden Is Controlled by Mural Cell-β3-Integrin Regulated Crosstalk with Tumor Cells

Cited by 63 publications

References 76 publications

The roles of integrins in cancer

The roles of integrins in cancer

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Isolation of Murine Primary Aortic Smooth Muscle Cells

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