Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma

Mitsuhashi, Noboru; Shimizu, Hiroaki; Ohtsuka, Masayuki; Wakabayashi, Yasuo; Ito, Hiroshi; Kimura, Fumio; Yoshidome, Hiroyuki; Kato, Atsushi; Nukui, Yuji; Miyazaki, Masaru

doi:10.1053/jhep.2003.50204

Cited by 164 publications

(128 citation statements)

References 35 publications

(44 reference statements)

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“…There is evidence that expression of VEGF messenger RNA (mRNA) is well correlated with VEGF protein expression in human hepatocellular carcinoma. 34,35 It also has been reported that ANG1, ANG2, and TIE2 RNA expression data were concordant with the corresponding protein expression data in human hepatocellular carcinoma and in rheumatoid arthritis. 35,36 We also found good agreement between RNA and protein expression data for the four angiogenesis-related molecules investigated (Fig.…”

Section: Discussionmentioning

confidence: 61%

Hepatic expression ofANG2 RNA in metastatic colorectal cancer

et al. 2004

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We examined the RNA content of the gene encoding angiopoietin (Ang)-2, a modifier of angiogenesis, in hepatic metastases of colorectal cancer (CRC) to explore the role of this protein in neovascularization of metastatic foci. Metastatic CRC exhibited notable blood flow and tumor vessel formation at tumor frontiers. Reverse-transcription polymerase chain reaction assays indicated that the ANG2 RNA content was greater in metastatic CRC than in primary CRC. Investigation of metastatic foci using laser capture microdissection revealed that the RNA content of ANG2, but not ANG1, increased from the bordering liver region to the periphery of the metastatic disease, and also from the periphery to the intermediate portion of the metastatic lesion; immunohistochemical analysis confirmed that there was a corresponding gradual increase in Ang-2 protein expression. Tie-2, a receptor for angiopoietins, was preferentially expressed in the bordering liver region rather than in metastatic CRC. Vascular endothelial growth factor (VEGF) also exhibited an expression pattern similar to that of Ang-2, and there was a significant correlation between the RNA content of ANG2 and that of VEGF in dissected samples (P ‫؍‬ .002). Western blot analysis suggested that expression of Ang-1, Ang-2, Tie-2, and VEGF may be regulated at a transcriptional level. C olorectal cancer (CRC) is a common malignancy worldwide. Although 84%-92% of patients with CRC are treated with surgical resection, more than half of these patients subsequently develop disease recurrence, 1 the most common type of recurrence being CRC metastatic to the liver, which often is associated with mortality. 2,3 Metastasis of CRC to the liver is a complex multistep process, which includes adherence of metastatic cells to endothelial cells (ECs), invasion across the endothelial basement membrane, cell proliferation, and neovascularization. 4 It was reported that tumor vessels appeared in human liver metastases when metastatic foci grew to 200 m in diameter and that the density of tumor vessels increased as tumor size increased. 5 Angiogenesis is essential for tumor growth and expansion, because the resulting blood vessels supply malignant cells with sufficient oxygen and nutrition. 6,7 Therefore, interruption of this process is considered to be a strategy for preventing CRC metastases to the liver.Recent studies have focused on novel endothelial growth factors such as angiopoietins (Ang), which are ligands for the endothelium-specific tyrosine kinase receptor Tie-2. 8 -10 Ang molecules play crucial roles in normal vascular development and in embryonic angio-

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Section: Discussionmentioning

confidence: 61%

Hepatic expression ofANG2 RNA in metastatic colorectal cancer

et al. 2004

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“…Indeed, more recent findings indicate that expression of angiopoietin 2, tissue factor and angiogenin are associated with tumor vascularity in HCC. [56][57][58] Similarly, our preliminary data showed that induction of different angiogenin isoforms correlated with the adenoma/carcinoma transition in c-Myc/TGF-a liver tumors. 59 In addition to its adhesive properties, E-cadherin displays the potential to suppress cell proliferation and transformation by inhibiting Wnt/bcatenin signaling.…”

Section: Discussionmentioning

confidence: 94%

Disregulation of E-cadherin in transgenic mouse models of liver cancer

Calvisi

Ladu

Conner

et al. 2004

Laboratory Investigation

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E-cadherin is a cell-cell adhesion molecule that plays a pivotal role in the development and maintenance of cell polarity. Disruption of E-cadherin-mediated adhesion represents a key step toward the invasive phenotype in a variety of solid tumors, including hepatocellular carcinoma (HCC). Here, we investigate whether deregulation of E-cadherin occurs along the multistep process of hepatocarcinogenesis in transgenic mouse models, including c-Myc, E2F1, c-Myc/TGF-a and c-Myc/E2F1 mice. Liver tumors from the transgenic mouse lines could be divided into two categories based on E-cadherin levels. Of 28, 20 (71.4%) c-Myc HCCs showed marked reduction of E-cadherin expression when compared with wild-type livers. In contrast, all of c-Myc/TGF-a and the majority of E2F1 and c-myc/E2F1 preneoplastic and neoplastic lesions exhibited overexpression of E-cadherin. Downregulation of E-cadherin was associated with promoter hypermethylation in seven of 20 c-Myc HCCs (35%), while no loss of heterozygosity at the E-cadherin locus was detected. Nuclear accumulation of b-catenin did not correlate with E-cadherin downregulation. Furthermore, c-Myc HCCs with reduced E-cadherin displayed upregulation of hypoxia-inducible factor-1a and vascular endothelial growth factor proteins. Importantly, loss of E-cadherin was associated with increased cell proliferation and higher microvessel density in c-Myc tumors. Taken together, these data suggest that loss of E-cadherin might favor tumor progression in relatively more benign HCC from c-Myc transgenic mice by stimulating neoplastic proliferation and angiogenesis under hypoxic conditions.

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“…Human brain (cerebellum) total RNA (BD Bioscience Clontech, Takaka Bio company, Shiga, Japan) was used as positive control of ApoC-1 (Lauer et al, 1988). Quantitative RT-PCR was carried out as previously described (Mitsuhashi et al, 2003) using LightCycler with LightCycler-Fast Start DNA Master SYBR Green I kit (Roche Diagnostics, Mannheim, Germany; see Supplementary Methods for detail).…”

Section: Isolation and Identification Of The Target Proteinsmentioning

confidence: 99%

Apolipoprotein C-1 maintains cell survival by preventing from apoptosis in pancreatic cancer cells

et al. 2007

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Pancreatic cancer still remains one of the most lethal diseases and establishment of new therapy is needed. The purpose of this study is to find novel factors involved in pancreatic cancer progression by proteomic approach. We compared pre-and postoperative serum protein profiling obtained from pancreatic cancer patients who had curative pancreatectomy using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The peak intensity levels of both 6630 and 6420 Da were significantly higher in the preoperative serum than in the postoperative serum (Po0.002). Sequential amino acid analysis identified these proteins to be apolipoprotein C-1 (ApoC-1). The high level of ApoC-1 in preoperative serum significantly correlated with poor prognosis. Furthermore, ApoC-1 was abundantly expressed in pancreas neoplastic epithelium, and was detected in the culture medium of the pancreatic cancer cell line in vitro, which suggests that cancer cells secrete ApoC-1. Inhibition of ApoC-1 expression by short interfering RNA suppressed cell proliferation and induced apoptosis of pancreatic cancer cells. The specific expression of ApoC-1 and its role in preventing from spontaneous apoptosis in pancreatic cancer cells suggest that ApoC-1 contributes to the aggressiveness of pancreatic cancer and will be useful as a new therapeutic target.

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Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma

Cited by 164 publications

References 35 publications

Hepatic expression ofANG2 RNA in metastatic colorectal cancer

Hepatic expression ofANG2 RNA in metastatic colorectal cancer

Disregulation of E-cadherin in transgenic mouse models of liver cancer

Apolipoprotein C-1 maintains cell survival by preventing from apoptosis in pancreatic cancer cells

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