Impaired endothelial shear stress induces podosome assembly<i>via</i>VEGF up‐regulation

Fey, Theres; Schubert, Kai; Schneider, Holger; Fein, Evelyn; Kleinert, Eike Christian; Pohl, Ulrich; Dendorfer, Andreas

doi:10.1096/fj.201500091r

Cited by 14 publications

(13 citation statements)

References 57 publications

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“…Meanwhile, ATOH8 advances HK2 transcription, which not only enhances the mitochondrial binding of HK2 to VDAC, but also inhibits ROS production through activating glycolysis. Both ultimately contribute to the survival of CRC m-CTCs metastasis directly by acting on cytokines and their receptors in tumour cells, such as VEGF, IL11, and IGF-2 [32,53,55]. These suggest that the VEGF signalling pathway may serve as the bridge between LSS and ATOH8, and we did confirm that LSS induced the VEGF-VEGFR2 pathway, which regulated the ATOH8mediated survival of m-CTCs.…”

Section: Discussionsupporting

confidence: 52%

“…Furthermore, to clarify the effect of LSS on CTC survival in more detail, we elucidated the mechanobiological mechanism of ATOH8-meditated response to LSS in CRC m-CTCs. In the past, scholars discovered that LSS promoted VEGF secretion and inhibited cell apoptosis in endothelial cells [52][53][54]. Moreover, increasing evidence has indicated that LSS mediates tumour Mechanically, in CRC m-CTCs responding to LSS stimulation, VEGF activates the downstream AKT pathway by acting on the VEGFR2 receptor, thereby facilitating ATOH8 expression.…”

Section: Discussionmentioning

confidence: 99%

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Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

Huang

et al. 2020

J Exp Clin Cancer Res

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Background: Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; however, the underlying mechanisms remain poorly understood. Methods: In view of the scarcity of CTCs in the bloodstream, suspended colorectal cancer cells were flowed into the cyclic laminar shear stress (LSS) according to previous studies. Then, we detected these suspended cells with a CK8+/CD45−/DAPI+ phenotype and named them mimic circulating tumour cells (m-CTCs) for subsequent CTCs related researches. Quantitative polymerase chain reaction, western blotting, and immunofluorescence were utilised to analyse gene expression change of m-CTCs sensitive to LSS stimulation. Additionally, we examined atonal bHLH transcription factor 8 (ATOH8) expressions in CTCs among 156 CRC patients and mice by fluorescence in situ hybridisation and flow cytometry. The pro-metabolic and pro-survival functions of ATOH8 were determined by glycolysis assay, live/dead cell vitality assay, anoikis assay, and immunohistochemistry. Further, the concrete up-anddown mechanisms of m-CTC survival promotion by ATOH8 were explored. Results: The m-CTCs actively responded to LSS by triggering the expression of ATOH8, a fluid mechanosensor, with executive roles in intravascular survival and metabolism plasticity. Specifically, ATOH8 was upregulated via activation of VEGFR2/AKT signalling pathway mediated by LSS induced VEGF release. ATOH8 then transcriptionally activated HK2-mediated glycolysis, thus promoting the intravascular survival of colorectal cancer cells in the circulation. Conclusions:This study elucidates a novel mechanism that an LSS triggered VEGF-VEGFR2-AKT-ATOH8 signal axis mediates m-CTCs survival, thus providing a potential target for the prevention and treatment of hematogenous metastasis in CRC.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

Huang

et al. 2020

J Exp Clin Cancer Res

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“…Our results demonstrated that only Erk1/2 and not Akt plays an indispensable role in KGF-induced podosome formation, which is in accordance with Gu's study (Gu et al 2007). However, Akt has also been reported to contribute to the assembly of podosomes in multiple cell types including osteoclasts and endothelial cells (Fey et al 2016;Kung et al 2012;Shinohara et al 2012). Various reasons can explain the diversity of regulatory mechanisms for podosome formation.…”

Section: Discussionmentioning

confidence: 99%

KGF induces podosome formation via integrin-Erk1/2 signaling in human immortalized oral epithelial cells

Liu

Ren

et al. 2018

Preprint

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Statement: Human immortalized oral epithelial cells can form podosomes after stimulation with KGF during which integrin-Erk1/2 signaling play essential roles. AbstractOur recent study established the role of integrins in KGF-induced oral epithelial adhesion and rete peg elongation. However, how extracellular matrix remodeling cooperates with the increased epithelial adhesion during rete peg elongation has yet to be determined. Podosomes are cell-matrix contact structures that combine several abilities, including adhesion and matrix degradation. In the present study, we identified podosome formation at the ventral side of human immortalized oral epithelial cells (HIOECs) upon KGF treatment. Moreover, podosomal components colocalized with the F-actin-cortactin complex and matrix degradation assays demonstrated the ability of the F-actin-cortactin complex to degrade matrix. Inhibition both of integrin subunits β4 and β1 with specific blocking antibodies and inhibition of Erk1/2 abrogated the KGF-induced podosome formation. Notably, knockdown of integrin subunits β4 and β1 with specific siRNA downregulated the phosphorylation levels of Erk1/2. In contrast, inhibition of both Erk1/2 could upregulate the expression of integrin subunits β4 and β1. These results demonstrate that KGF induces podosome formation via integrin-Erk1/2 signaling in HIOECs, suggesting a novel mechanism by which integrins enhance oral epithelial adhesion and rete peg elongation.

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“…Mechanical stimuli act either as shear stress tangential to the vessel or as mechanical strain transversal to the direction of blood flow on the ECs [ 98 ]. Continuous shear stress initiated by the physiological blood flow decreases the VEGF expression, leading to an inhibition of filopodia formation [ 98 , 99 ]. By subsequent inhibition of the EC migration activity and tip cell-induced matrix remodeling the vessel elongation is stopped, and the vessel is stabilized [ 99 ].…”

Section: Vessel Stabilizationmentioning

confidence: 99%

Mechanical Aspects of Angiogenesis

Kretschmer

Rüdiger

Zahler

2021

Cancers

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Angiogenesis is of high clinical relevance as it plays a crucial role in physiological (e.g., tissue regeneration) and pathological processes (e.g., tumor growth). Besides chemical signals, such as VEGF, the relationship between cells and the extracellular matrix (ECM) can influence endothelial cell behavior during angiogenesis. Previously, in terms of the connection between angiogenesis and mechanical factors, researchers have focused on shear forces due to blood flow. However, it is becoming increasingly important to include the direct influence of the ECM on biological processes, such as angiogenesis. In this context, we focus on the stiffness of the surrounding ECM and the adhesion of cells to the ECM. Furthermore, we highlight the mechanical cues during the main stages of angiogenesis: cell migration, tip and stalk cells, and vessel stabilization. It becomes clear that the different stages of angiogenesis require various chemical and mechanical cues to be modulated by/modulate the stiffness of the ECM. Thus, changes of the ECM during tumor growth represent additional potential dysregulations of angiogenesis in addition to erroneous biochemical signals. This awareness could be the basis of therapeutic approaches to counteract specific processes in tumor angiogenesis.

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Impaired endothelial shear stress induces podosome assemblyviaVEGF up‐regulation

Cited by 14 publications

References 57 publications

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

KGF induces podosome formation via integrin-Erk1/2 signaling in human immortalized oral epithelial cells

Mechanical Aspects of Angiogenesis

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