Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma

Marschall, Zofia von; Cramer, Thorsten; Höcker, Michael; Finkenzeller, Günter; Wiedenmann, Bertram; Rosewicz, Stefan

doi:10.1136/gut.48.1.87

Cited by 159 publications

(104 citation statements)

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“…After TACE, tumor cells are exposed to an extremely hypoxic or even anoxic environment. Because of ischemic damage, vascular endothelial growth factor and basic fibroblast growth factor, which act synergistically, are overexpressed after TACE (21,23). Levels of these angiogenic factors were found to be significant predictors of clinical outcomes in patients with HCC (26,27).…”

Section: Discussionmentioning

confidence: 98%

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Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using¹⁸F-FDG PET/CT

Kim¹,

Kim²,

Shin³

et al. 2010

J Nucl Med

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This study aimed to evaluate the metabolic characteristics of lipiodolized hepatocellular carcinomas (HCCs) and the diagnostic accuracy of 18 F-FDG PET/CT in assessing the viability of lipiodolized HCCs. Methods: Thirty-six patients (age range, 32-73 y) with 38 lipiodolized HCCs who had undergone transcatheter arterial chemoembolization (TACE) with lipiodol before 18 F-FDG PET/CT (2-434 d) and 55 patients (age range, 36-77 y) with 57 treatment-naïve HCCs who had not been treated with TACE were retrospectively studied. All patients underwent hepatic lobectomy or transplantation within 1 mo after PET/CT and multiphasic contrast-enhanced CT. 18 F-FDG uptake by lipiodolized and naïve HCCs was compared and correlated with tumor size, pathologic grade, serum a-fetoprotein (AFP) concentration, and time interval between TACE and PET/CT. The diagnostic accuracy of PET/CT and contrast-enhanced CT in evaluating the viability of lipiodolized HCC was compared. Results: Histologic examination showed 30 viable and 8 nonviable lipiodolized HCCs. Of the 30 viable tumors, 19 showed increased, 10 similar, and 1 decreased 18 F-FDG uptake. Of the 8 nonviable HCCs, 3 showed increased and 5 decreased 18 F-FDG uptake. Uptake by viable lipiodolized HCCs was correlated with tumor size (P , 0.05) but not correlated with pathologic grade, AFP concentration, or interval between TACE and PET/ CT. In contrast, 18 F-FDG uptake by naïve HCCs was significantly correlated with tumor size and pathologic grade (P , 0.05 for each comparison). When lipiodolized HCCs with 18 F-FDG uptake that was greater than or similar to that in the surrounding normal liver were considered viable, the diagnostic sensitivity of PET/CT and contrast-enhanced CT in the early postembolic period (,3 mo) was 100% and 94%, respectively, and that in the late postembolic period was 93% and 79%, respectively. The specificity of 18 F-FDG PET/CT and contrastenhanced CT was 63% and 100%, respectively, in the acute period. Three viable lipiodolized HCCs with high AFP concentration were true-positives on PET/CT but false-negatives on contrast-enhanced CT images. Conclusion: After TACE, 18 F-FDG uptake in lipiodolized HCCs was not correlated with pathologic grade, in contrast to uptake in treatment-naïve HCCs. 18 F-FDG PET/CT showed a high diagnostic sensitivity in assessing the viability of lipiodolized HCCs, with moderate specificity. This method may be useful in determining the viability of lipiodolized HCCs in patients with increased serum AFP concentration or normal results on contrast-enhanced CT images.

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Section: Discussionmentioning

confidence: 98%

“…TACE has been shown to stimulate tumor angiogenesis, thus increasing the proliferative activity of tumor cells to some degree (21)(22)(23)(24)(25). After TACE, tumor cells are exposed to an extremely hypoxic or even anoxic environment.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using¹⁸F-FDG PET/CT

Kim¹,

Kim²,

Shin³

et al. 2010

J Nucl Med

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“…COX-2 has been shown to be induced by hypoxia 32 which was also involved in angiogenesis of hepatocellular carcinoma. 33 There was active hepatitis present in some hepatocellular carcinoma tissues. Inflammatory cytokines like tumor necrosis factor a may thus stimulate COX-2 upregulation.…”

Section: Discussionmentioning

confidence: 99%

Expression of HBx and COX-2 in chronic hepatitis B, cirrhosis and hepatocellular carcinoma: implication of HBx in upregulation of COX-2

et al. 2004

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Hepatitis B virus is a major etiological factor of hepatocellular carcinoma, but the underlying mechanisms remain unclear. We have previously demonstrated that upregulation of cyclooxygenase (COX)-2 in chronic hepatitis B persisted despite successful antiviral therapy. In this study, we investigated the relationship between the transactivator HBx and COX-2 in hepatitis B virus-associated chronic liver diseases. Expressions of HBx and COX-2 in tissue specimens were determined by single and double immunohistochemistry. The effects of HBx on COX-2 and prostaglandin E 2 production were studied by transfection. HBx was expressed in 11/11 (100%) of chronic hepatitis B, 23/23 (100%) of cirrhosis, and 18/23 (78%) of hepatocellular carcinoma, whereas no immunoreactivity was found in four nonalcoholic steato-hepatitis controls. COX-2 expression was also detected in all specimens of liver lesions except in only 29% of poorly differentiated hepatocellular carcinoma. Significant correlation between HBx and COX-2 immunoreactivity scores was found in different types of chronic liver diseases (chronic hepatitis B, rs ¼ 0.68; cirrhosis, rs ¼ 0.57; hepatocellular carcinoma, rs ¼ 0.45). Double immunohistochemistry showed colocalization of HBx and COX-2 in hepatic parenchymal cells. Similar to COX-2, there was no significant change in HBx expression in patients with chronic hepatitis B after interferon and lamivudine therapy when hepatitis B virus DNA became undetectable and inflammation subsided. Transfection of Hep3B hepatocellular carcinoma cells with HBx increased COX-2 expression and prostaglandin E 2 production. HBx was localized mainly in the cytoplasm and less in nucleus, as found in the liver lesions. In conclusion, our results strongly suggested that there was a close relationship between HBx and COX-2. COX-2 might represent an important cellular effector of HBx that contributes to hepatitis B virusassociated hepatocarcinogenesis.

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“…5,6 Expression of VEGF is regulated through both transcriptional and posttranscriptional mechanisms. 7 VEGF transcription is activated by hypoxia 8,9 and growth factors. 10 However, the induction of VEGF is transient and returns to baseline levels through post-transcriptional regulation.…”

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confidence: 99%

Tristetraprolin regulates expression of VEGF and tumorigenesis in human colon cancer

Lee

Son

Lee

et al. 2009

Intl Journal of Cancer

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Tristetraprolin (TTP) is an AU‐rich element‐binding protein that regulates mRNA stability. Here, we report that TTP suppress the growth of human colon cancer cells both in vivo and in vitro by regulating of the expression of vascular endothelial growth factor (VEGF). TTP protein expression in human colonic tissues was markedly decreased in colonic adenocarcinoma compared with in normal mucosa and adenoma. VEGF expression was higher in colonic adenocarcinoma than in normal mucosa and adenoma. Specific inhibition of TTP expression by RNA‐interference increased the expression of VEGF in cultured human colon cancer cells, and TTP overexpression markedly decreased it. In addition, elevated expression of TTP decreased the expression level of luciferase linked to a 3′ terminal AU‐rich element (ARE) of VEGF mRNA. Colo320/TTP cells overexpressing TTP grew slowly in vitro and became tumors small in size when xenografted s.c into nude mice. These findings demonstrate that TTP acts as a negative regulator of VEGF gene expression in colon cancer cells, suggesting that it can be used as novel therapeutic agent to treat colon cancer.

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Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma

Abstract: These data suggest hypoxia as a central stimulus of angiogenesis in human HCC through upregulation of VEGF gene expression by at least two distinct molecular mechanisms: activation of VEGF gene transcription and an increase in VEGF mRNA stability.

Cited by 159 publications

References 48 publications

Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using¹⁸F-FDG PET/CT

Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using¹⁸F-FDG PET/CT

Expression of HBx and COX-2 in chronic hepatitis B, cirrhosis and hepatocellular carcinoma: implication of HBx in upregulation of COX-2

Tristetraprolin regulates expression of VEGF and tumorigenesis in human colon cancer

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Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma

Abstract: These data suggest hypoxia as a central stimulus of angiogenesis in human HCC through upregulation of VEGF gene expression by at least two distinct molecular mechanisms: activation of VEGF gene transcription and an increase in VEGF mRNA stability.

Cited by 159 publications

References 48 publications

Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using18F-FDG PET/CT

Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using18F-FDG PET/CT

Expression of HBx and COX-2 in chronic hepatitis B, cirrhosis and hepatocellular carcinoma: implication of HBx in upregulation of COX-2

Tristetraprolin regulates expression of VEGF and tumorigenesis in human colon cancer

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Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using¹⁸F-FDG PET/CT

Evaluation of Metabolic Characteristics and Viability of Lipiodolized Hepatocellular Carcinomas Using¹⁸F-FDG PET/CT