Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

Jean, Christine; Chen, Xiao Lei; Nam, Ju-Ock; Tancioni, Isabelle; Uryu, Sean; Lawson, Christine; Ward, Kristy; Walsh, Charles J.; Miller, Nichol L.G.; Ghassemian, Majid; Turowski, Patric; Dejana, Elisabetta; Weis, Sara M.; Cheresh, David A.; Schlaepfer, David D.

doi:10.1083/jcb.201307067

Cited by 153 publications

(179 citation statements)

References 51 publications

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…2). Our data are consistent with previous studies that demonstrate that FAK and its signaling partners promote systemic and lung vascular permeability (19)(20)(21)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62); however, our study, to our knowledge, reports the novel Figure 7. Proposed schematics of N-WASP-mediated actin cytoskeletal dynamics and permeability derangements during lung injury.…”

Section: Discussionsupporting

confidence: 55%

Neuronal Wiskott‐Aldrich syndrome protein regulates TGF‐β1‐mediated lung vascular permeability

et al. 2016

View full text Add to dashboard Cite

TGF-b1 induces an increase in paracellular permeability and actin stress fiber formation in lung microvascular endothelial and alveolar epithelial cells via small Rho GTPase. The molecular mechanism involved is not fully understood. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) has an essential role in actin structure dynamics. We hypothesized that N-WASP plays a critical role in these TGF-b1-induced responses. In these cell monolayers, we demonstrated that N-WASP down-regulation by short hairpin RNA prevented TGF-b1-mediated disruption of the cortical actin structure, actin stress filament formation, and increased permeability. Furthermore, N-WASP down-regulation blocked TGF-b1 activation mediated by IL-1b in alveolar epithelial cells, which requires actin stress fiber formation. Control short hairpin RNA had no effect on these TGF-b1-induced responses. TGF-b1-induced phosphorylation of Y256 of N-WASP via activation of small Rho GTPase and focal adhesion kinase mediates TGF-b1-induced paracellular permeability and actin cytoskeleton dynamics. In vivo, compared with controls, N-WASP down-regulation increases survival and prevents lung edema in mice induced by bleomycin exposure-a lung injury model in which TGF-b1 plays a critical role. Our data indicate that N-WASP plays a crucial role in the development of TGF-b1-mediated acute lung injury by promoting pulmonary edema via regulation of actin cytoskeleton

show abstract

Section: Discussionsupporting

confidence: 55%

Neuronal Wiskott‐Aldrich syndrome protein regulates TGF‐β1‐mediated lung vascular permeability

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The effect of tumor-associated endothelial cells on the ability of tumor cells to grow and metastasize is not completely clear. Numerous studies hypothesize that in vivo tumor-associated endothelial cells receive biological signals from tumor cells and other tumor-associated stromal cells by absorbing paracrine factors, and subsequently induce tumor angiogenesis, which is essential for tumor growth and metastasis (7). In accordance with this hypothesis, the present study established a bionic 3D co-culture system using microfluidic chip technology in order to simulate the tumor microenvironment in vivo.…”

Section: Introductionmentioning

confidence: 54%

Acute effect of lactic acid on tumor-endothelial cell metabolic coupling in the tumor microenvironment

Zhu

Wang

et al. 2016

Oncology Letters

View full text Add to dashboard Cite

Abstract. The present study aimed to systematically analyze alterations in the expression of mitochondrial-associated proteins in human bladder cancer T24 cells co-cultured with tumor-associated human umbilical vein endothelial cells (HUVECs), and to investigate the characteristics of bladder cancer cell energy metabolism. The present study used the following techniques: A co-culture system of T24 cells and HUVECs was constructed using a microfluidic chip as a 3D co-culture system; the concentration of lactic acid in the medium of the cells was determined using an automatic microplate reader; a qualitative analysis of mitochondria-associated protein expression was performed by immunofluorescent staining; and a quantitative analysis of mitochondrial-associated protein expression was conducted using western blotting. The present results revealed that between the control groups (monoculture of T24 cells or HUVECs), the mitochondrial-associated protein fluorescence intensity was increased in the HUVECs compared with the T24 cells. The fluorescence intensity of mitochondrial-associated proteins in the HUVEC control group was increased compared with the HUVECs in the experimental co-culture group. In the T24 cells, the protein fluorescence intensity was increased in the experimental co-culture group compared with the control group. In addition, the expression of mitochondria-associated proteins was increased in HUVECs compared with T24 cells in the control groups, while T24 cells in the experimental co-culture group had an increased expression compared with HUVECs in the experimental group (P<0.05). For T24 cells, the expression of mitochondrial-associated proteins was increased in the experimental group compared with the control group, and contrasting results were observed for the HUVECs (P<0.05). Determination of lactic acid concentration demonstrated that lactic acid concentration was highest in the experimental co-culture group, followed by the T24 control group and the HUVEC control group. In conclusion, the present study demonstrated that energy metabolism of the bladder tumor cells does not parallel the 'Warburg effect', since even under sufficient oxygen conditions the tumor cells still undergo glycolysis. Additionally, bladder tumor cells have an efficient oxidative phosphorylation process, wherein tumor cells promote glycolysis in adjacent interstitial cells, thereby causing increased formation of nutritional precursors. These high-energy metabolites are transferred to adjacent tumor cells in a specified direction and enter the Krebs Cycle. Ultimately, oxidative phosphorylation increases, and sufficient ATP is produced.

show abstract

“…Although our studies utilize cell-type-specific inhibition and point to a defined mechanism, FAK inhibitors could have complex effects on atherosclerosis. FAK-KD transgenic mice show reduced endothelial cell permeability compared to wild-type mice, which should decrease the infiltrating leukocyte population during the progression of atherosclerosis Jean et al, 2014). Inhibiting FAK in smooth muscle cells results in decreased proliferation and motility, features that drive stenotic lesions but protect atherosclerotic plaques from rupturing.…”

Section: Discussionmentioning

confidence: 99%

Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression

Yurdagul

Sulzmaier

Chen

et al. 2016

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor κB (NF-κB) activation, proinflammatory gene expression and monocyte adhesion. Like for other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK, also known as PTK2) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-κB signaling has yet to be revealed. We now show that oxLDL induces NF-κB activation and VCAM-1 expression through FAK-dependent IκB kinase β (IKKβ, also known as IKBKB) activation. We further identify FAK-dependent activation of p90 ribosomal S6 kinase family proteins (RSK) as a crucial mediator of oxLDL-dependent IKKβ and NF-κB signaling, as inhibiting RSK blocks oxLDL-induced IKKβ and NF-κB activation, VCAM-1 expression and monocyte adhesion. Finally, transgenic mice containing a kinase-dead mutation in FAK specifically in the endothelial cells show reduced RSK activity, decreased VCAM-1 expression and reduced macrophage accumulation in regions of early atherosclerosis. Taken together, our data elucidates a new mechanism whereby oxLDL-induced endothelial FAK signaling drives an ERK-RSK pathway to activate IKKβ and NF-κB signaling and proinflammatory gene expression.

show abstract

Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

Abstract: Endothelial cell focal adhesion kinase is a key intermediate between c-Src and the regulation of endothelial cell barrier function in the control of tumor metastasis.

Cited by 153 publications

References 51 publications

Neuronal Wiskott‐Aldrich syndrome protein regulates TGF‐β1‐mediated lung vascular permeability

Neuronal Wiskott‐Aldrich syndrome protein regulates TGF‐β1‐mediated lung vascular permeability

Acute effect of lactic acid on tumor-endothelial cell metabolic coupling in the tumor microenvironment

Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression

Contact Info

Product

Resources

About