Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer.

Abstract

BACKGROUND:

Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with angiogenesis and poor outcome. TXS has been identified as a potential therapeutic target in NSCLC. This study examines a link between TXS expression, angiogenesis, and survival in NSCLC.

METHODS:

TXS and VEGF metabolite levels were measured in NSCLC serum samples (n=46) by EIA. TXB2 levels were correlated with VEGF. A 204-patient TMA was stained for TXS, VEGF, and CD-31 expression. Expression was correlated with a range of clinical parameters, including overall survival. TXS expression was correlated with VEGF and CD-31. Stable TXS clones were generated and the effect of overexpression on tumor growth and angiogenesis markers was examined in-vitro and in-vivo (xenograft mouse model).

RESULTS:

Serum TXB2 levels were correlated with VEGF (p<0.05). TXS and VEGF were expressed to a varying degree in NSCLC tissue. TXS was associated with VEGF (p<0.0001) and microvessel density (CD-31; p<0.05). TXS and VEGF expression levels were higher in adenocarcinoma (p<0.0001) and female patients (p<0.05). Stable overexpression of TXS increased VEGF secretion in-vitro. While no significant association with patient survival was observed for either TXS or VEGF in our patient cohort, TXS overexpression significantly (p<0.05) increased tumor growth in-vivo. TXS overexpression was also associated with higher levels of VEGF, microvessel density, and reduced apoptosis in xenograft tumors.

CONCLUSION:

TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis.

• Authors: Mary Clare Cathcart, Kathy Gately, Robert Cummins, Clive Drakeford, Elaine W Kay, Kenneth J O'Byrne, Graham P Pidgeon
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1842 Issue 5 Pg. 747-55 (May 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24480048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Vascular Endothelial Growth Factor A
• Thromboxane B2
• Thromboxane-A Synthase

Topics

• Carcinoma, Non-Small-Cell Lung (blood supply, enzymology, metabolism)
• Humans
• Lung Neoplasms (blood supply, enzymology, metabolism)
• Neovascularization, Pathologic
• Thromboxane B2 (metabolism)
• Thromboxane-A Synthase (metabolism)
• Tissue Array Analysis
• Vascular Endothelial Growth Factor A (metabolism)