Angiopoietin‐2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma

Kuboki, Satoshi; Shimizu, Hiroaki; Mitsuhashi, Noboru; Kusashio, Kimihiko; Kimura, Fumio; Yoshidome, Hiroyuki; Ohtsuka, Masayuki; Kato, Atsushi; Yoshitomi, Hideyuki; Miyazaki, Masaru

doi:10.1111/j.1440-1746.2007.05175.x

Cited by 29 publications

(26 citation statements)

References 33 publications

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“…Increased circulating levels of angiogenic factors such as VEGF and Angiopoietin-2 (Ang2) have been reported in patients with HCC and correlate with poor prognosis (25)(26)(27)(28). Correspondingly, tumor-bearing iAST mice revealed signs of active angiogenesis: Circulating levels of VEGF were upregulated in iASTinduced tumor-bearing mice ( Fig.…”

Section: Tumor Nodules Establish a Functional Neovasculature With Incmentioning

confidence: 89%

An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

Runge

Wieland

et al. 2014

Cancer Research

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The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large Tantigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. Cancer Res; 74(15); 4157-69. Ó2014 AACR.

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Section: Tumor Nodules Establish a Functional Neovasculature With Incmentioning

confidence: 89%

An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

Runge

Wieland

et al. 2014

Cancer Research

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“…Tumor overexpression of Ang2 was associated with vascular invasion, tumor size microvessel density level, poorly prognosis HCC [108,109] and poor differentiated tumor [110] . Preoperative presence of Ang2 in the hepatic vein was also associated with portal invasion and poor outcome in HCC resected patients [111] . In a small uncontrolled cohort of patients treated with sorafenib for advanced HCC, the authors reported that Ang2 could predict the outcome [112] .…”

Section: Hepatocyte Growth Factormentioning

confidence: 92%

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Bouattour

Payancé

Wassermann

2015

WJH

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Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimi zing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.

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“…Moreover, nude mice injected with a HCC cell line overexpressing Ang-2 displays faster tumor growth with greater neovascularisation in the tumor [37,38]. Additionally, a high preoperative Ang-2 level in the hepatic vein is a good predictor for portal invasion and also poor prognosis in human HCC [39]. Tie-2 receptor depends on the balance of its ligands Ang-2, which may control vascular plasticity, angiogenesis, and vascular permeability [40].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Induces Angiogenic Factors Production Partly Via AT1/JAK2/STAT3/SOCS3 Signaling Pathway in MHCC97H Cells

Ji¹,

Wang

et al. 2012

Cell Physiol Biochem

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Angiotensin II (Ang II) has been shown to function as a key role in neovascularization of hepatocellular carcinoma (HCC), but little is known its underlying mechanisms. The aim of this study was to explore the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in Ang II-induced HCC angiogenic factors production. Herein, we found that Ang II upregulated angiogenic factors production such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and Tie-2 in MHCC97H cells in a time- and concentration-dependent manner. And VEGF and Ang-2 caused a significant increase in angiogenic tube formation. Especially, Ang II-induced angiogenic tube formation was blunted by VEGF small interfering RNA (siRNA) and Ang-2 siRNA, respectively. The JAK2 inhibitor AG490 partly attenuated the effects of Ang II. Moreover, Ang II- induced JAK2 and STAT3 phosphorylation was significantly suppressed by losartan but not PD123319. Meanwhile, STAT3 phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression induced by Ang II were evidently impaired by AG490. More importantly, SOCS3 siRNA remarkably reinforced Ang II-induced VEGF, Ang-2 and Tie-2 generation in MHCC97H cells. Taken together, the present study demonstrates that Ang II induces angiogenic factors production partly via AT1/ JAK2/STAT3/SOCS3 signaling pathway in MHCC97H cells. These findings may provide important insights into the potential mechanism with respect to the AT1/ JAK2/ STAT3/SOCS3 signaling pathway associated with Ang II-induced angiogenesis in the pathogenesis of HCC.

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Angiopoietin‐2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma

Abstract: Preoperative hepatic venous Ang-2 levels may be a good predictor for portal vein invasion and also prognosis in patients with HCC.

Cited by 29 publications

References 33 publications

An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Angiotensin II Induces Angiogenic Factors Production Partly Via AT1/JAK2/STAT3/SOCS3 Signaling Pathway in MHCC97H Cells

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