Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma

Huang, Shih-Pei; Wu, Ming–Shiang; Shun, Chia‐Tung; Wang, Hsiu–Po; Hsieh, Chang‐Yao; Kuo, Min-Liang; Lin, Jaw–Town

doi:10.1007/s11373-004-8177-5

Cited by 105 publications

(86 citation statements)

References 41 publications

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“…Reactive oxygen species regulate HIF stability and transcriptional activity under hypoxia and normoxia (Pouyssegur and Mechta-Grigoriou, 2006). Inflammation-mediated COX-2 expression is an early feature of Barrett's carcinogenesis (Morris et al, 2001) and, in a gastric cancer model, the COX-2/PGE2/HIF-1/VEGF pathway was shown to contribute to tumour angiogenesis (Huang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

Griffiths

Pritchard²,

McGrath³

et al. 2007

Br J Cancer

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Hypoxia-associated markers are involved in the progression of several malignancies, but are relatively unstudied in Barrett's carcinogenesis. Our aim was to assess the immunohistochemical expression of hypoxia-inducible factor (HIF)-1a, HIF-2a, erythropoietin (Epo), Epo receptor (Epo-R), Glut-1 and vascular endothelial growth factor (VEGF) along with Ki67/MIB-1 in the Barrett's metaplasia -dysplasia -adenocarcinoma sequence. Endoscopic biopsies of normal squamous epithelium (NSE) (n ¼ 20), columnar-lined oesophagus (CLO) (n ¼ 15), CLO with intestinal metaplasia (n ¼ 20), dysplasia (n ¼ 17) and Barrett's type adenocarcinoma (n ¼ 20) were obtained. Immunohistochemistry was performed on the paraffin-embedded tissue. A score was calculated for each marker (range 0À300) by multiplying intensity (none 0, weak 1, moderate 2, strong 3) by percentage of expression (range 0 -100). Significant increases in the expression of HIF-2a (P ¼ 0.014), VEGF (Po0.0001), Epo-R (Po0.0001) and Ki67 (Po0.0001) were found as tissue progressed from NSE to adenocarcinoma. HIF-2a was expressed late in the sequence and was only seen in dysplasia and adenocarcinoma. High HIF-2a expression was seen in 12 out of 20 Barrett's type adenocarcinoma. The late expression of HIF-2a in the Barrett's carcinogenesis sequence and its high expression in adenocarcinoma suggest that it is worth further investigation as a marker of disease progression and therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

Griffiths

Pritchard²,

McGrath³

et al. 2007

Br J Cancer

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“…The inhibition of HIF-1α function results in the reduction of VEGF secretion in vitro, and in the inhibition of tumor growth and angiogenesis in vivo [31]. VEGF and HIF-1α are upregulated by cyclooxygenase-2 (COX-2) overexpression through a prostaglandin E2 (PGE2)-dependent pathway [32]. We found here that the increased expression of HIF-1α and VEGF had no association with the clinicopathological findings on prognosis, except for the rare occurrence of distant metastasis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma

et al. 2006

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“…Previous studies show that VEGF and HIF-1· accelerate angiogenesis by upregulating HO-1 in endothelial cells (17,28,29). However, it is unclear whether HO-1 is associated with angiogenesis and other angiogenic factors in UC of the bladder.…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase-1 promotes angiogenesis in urothelial carcinoma of the urinary bladder

Miyake

Fujimoto²,

Anai³

et al. 2011

Oncol Rep

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Abstract. Angiogenesis is necessary for the growth, invasion, and metastasis of solid tumors. Previous studies have shown that heme oxygenase-1 (HO-1) plays an important role in angiogenesis in both normal and cancerous cells, such as vascular endothelial cells and pancreatic cancer cells, respectively. In this study, we analyzed the role of HO-1 and other angiogenic factors in urothelial carcinoma of the bladder. Specifically, we used real-time reverse transcription polymerase chain reaction (PCR) and Western blotting to investigate the upregulation of 7 angiogenic factors, namely, HO-1, vascular endothelial growth factor (VEGF), hypoxiainducible factor (HIF)-1·, HIF-2·, cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) under hypoxic conditions in the T24 urothelial carcinoma cell line. We also used enzyme-linked immunosorbent assay (ELISA) to measure the amount of VEGF secreted into the growth media. In addition, we administered an HO-1 inhibitor, zinc protoporphyrin IX, to mice with subcutaneous T24 tumors to assess the modulation of angiogenesis in solid tumors in vivo. We also performed immunohistochemical analyses of 23 primary bladder cancer specimens with high-grade tumors infiltrating into the stroma (pT1) for expression of HO-1, VEGF, HIF-1·, HIF-2·, COX-2, and CD31. Image analysis of CD31 staining was performed to estimate microvessel density (MVD), a measure of angiogenesis. Hypoxic conditions induced upregulation of HO-1, VEGF, HIF-1·, HIF-2·, and COX-2 in T24 cells and increased VEGF secretion, which could be suppressed by zinc protoporphyrin IX. In vivo, inhibition of HO-1 decreased tumor growth and MVD by suppressing angiogenic factors, particularly VEGF and HIF-1·. In clinical specimens of bladder cancer, high expression of HO-1 was correlated with high expression of HIF-1· (P=0.027) and high MVD (P=0.005), but not with VEGF expression (P=0.19). In conclusion, since overexpression of HO-1 promotes angiogenesis in urothelial carcinoma cells, HO-1 inhibitors could be used as novel therapeutics for urothelial carcinoma of the urinary bladder.

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Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma

Cited by 105 publications

References 41 publications

Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma

Heme oxygenase-1 promotes angiogenesis in urothelial carcinoma of the urinary bladder

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