Dataset Information

ICAM-1 Activates Platelets and Promotes Endothelial Permeability through VE-Cadherin after Insufficient Radiofrequency Ablation.

ABSTRACT: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) often leads to aggressive local recurrence and increased metastasis, and vascular integrity and platelets are implicated in tumor metastasis. However, whether interactions between endothelial cells and platelets induce endothelial permeability in HCC after insufficient RFA remains unclear. Here, significantly increased CD62P-positive platelets and sP-selectin in plasma are observed in HCC patients after RFA, and tumor-associated endothelial cells (TAECs) activate platelets and are susceptible to permeability after heat treatment in the presence of platelets in vitro. In addition, tumors exhibit enhanced vascular permeability after insufficient RFA in mice; heat treatment promotes platelets-induced endothelial permeability through vascular endothelial (VE)-cadherin, and ICAM-1 upregulation in TAECs after heat treatment results in platelet activation and increased endothelial permeability in vitro. Moreover, the binding interaction between upregulated ICAM-1 and Ezrin downregulates VE-cadherin expression. Furthermore, platelet depletion or ICAM-1 inhibition suppresses tumor growth and metastasis after insufficient RFA in an orthotopic tumor mouse model, and vascular permeability decreases in ICAM-1^-/- mouse tumor after insufficient RFA. The findings suggest that ICAM-1 activates platelets and promotes endothelial permeability in TAECs through VE-cadherin after insufficient RFA, and anti-platelet and anti-ICAM-1 therapy can be used to prevent progression of HCC after insufficient RFA.

SUBMITTER: Kong J

PROVIDER: S-EPMC7887603 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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ICAM-1 Activates Platelets and Promotes Endothelial Permeability through VE-Cadherin after Insufficient Radiofrequency Ablation.

Kong Jian J Yao Changyu C Dong Shuying S Wu Shilun S Xu Yangkai Y Li Ke K Ji Liang L Shen Qiang Q Zhang Qi Q Zhan Rui R Cui Hongtu H Zhou Changping C Niu Haigang H Li Guoming G Sun Wenbing W Zheng Lemin L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210104 4

Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) often leads to aggressive local recurrence and increased metastasis, and vascular integrity and platelets are implicated in tumor metastasis. However, whether interactions between endothelial cells and platelets induce endothelial permeability in HCC after insufficient RFA remains unclear. Here, significantly increased CD62P-positive platelets and sP-selectin in plasma are observed in HCC patients after RFA, and tumor-associated en ...[more]

PMID: 33643788

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Project description:BackgroundThe mechanism regarding rapid progression of residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) has been preliminarily discussed. However, most studies have mainly focused on RFA-induced changes in the tumor cells. The present study was designed to determine whether tumor-associated endothelial cells (TAECs) could contribute to the invasiveness of HCC after insufficient RFA.MethodsTAECs were isolated from fresh HCC tissue and characterized. Morphological changes were observed in TAECs after heat treatment for 10 min. TAEC proliferation, migration and tube formation after heat treatment for 10 min at 37°C (control group), and 42 and 47°C (insufficient RFA groups) were examined. The differences in TAECs interactions with HepG2-GFP or HCCLM3-GFP cells among the two insufficient RFA groups and control group were evaluated. The expression of E-selectin, ICAM-1 and VCAM-1 in TAECs was measured. The effects of TAECs on the invasiveness of HepG2-GFP or HCCLM3-GFP cells after insufficient RFA were analyzed. The IL-6, IL-8, MCP-1 and GRO-α concentrations in conditioned medium from TAECs were measured after insufficient RFA. The associated signaling pathways of Akt, ERK1/2, STAT3 and NF-κB were analyzed in TAECs after insufficient RFA.ResultsTAECs expressed the EC-specific markers and took up complexes of Dil-Ac-LDL. Relative to the control group, the proliferation of TAECs was significantly inhibited and their migration and tube formation were significantly enhanced in the insufficient RFA groups. Significantly more HepG2-GFP or HCCLM3-GFP cells adhered to TACEs in these groups than in the control group (all P<0.001), via up-regulated expression of E-selectin, ICAM-1 and VCAM-1. TAECs promoted the invasiveness of HepG2-GFP or HCCLM3-GFP cells after insufficient RFA via the up-regulation of IL-6, IL-8, MCP-1 and GRO-α in conditioned medium (all P<0.05). Insufficient RFA enhanced the activities of Akt, ERK1/2 and NF-κB signaling pathways and inhibited STAT3 signaling pathways.ConclusionsInsufficient RFA enhanced TAEC migration and tube formation, and this may play a key role in the rapid growth of residual HCC. Increased expression of metastasis-related molecules in TAECs after insufficient RFA may be a potential mechanism for the metastasis of residual HCC.

Project description:RATIONALE:The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE:We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS:We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and ?-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/?-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS:These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

Dataset Information

ICAM-1 Activates Platelets and Promotes Endothelial Permeability through VE-Cadherin after Insufficient Radiofrequency Ablation.

Publications

ICAM-1 Activates Platelets and Promotes Endothelial Permeability through VE-Cadherin after Insufficient Radiofrequency Ablation.

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