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


CONCLUSIONS
TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis.
Department of Surgery, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland. Electronic address: cathcarm@tcd.ie.
Mary Clare
MC
Cathcart
Department of Clinical Medicine and Oncology, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland. Electronic address: KGately@stjames.ie.
Kathy
K
Gately
Department of Pathology, Beaumont Hospital, Dublin 9, Ireland. Electronic address: rcummins@rcsi.ie.
Robert
R
Cummins
Department of Surgery, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland. Electronic address: drakefoc@tcd.ie.
Clive
C
Drakeford
Department of Pathology, Beaumont Hospital, Dublin 9, Ireland. Electronic address: elainekay@beaumont.ie.
Elaine W
EW
Kay
Department of Clinical Medicine and Oncology, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland; Cancer and Aging Research Program, Queensland University of Technology, Brisbane, Queensland, Australia. Electronic address: Kenneth.O'Byrne@health.qld.gov.au.
Kenneth J
KJ
O'Byrne
Department of Surgery, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland. Electronic address: pidgeong@tcd.ie.
Graham P
GP
Pidgeon
D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000378:metabolism*; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase
Angiogenesis; CD-31; Non-small cell lung cancer; Thromboxane synthase; VEGF