title: Endothelin-1 is a novel prognostic factor in non-small cell lung cancer.
abstract: Endothelin-1 (ET-1) is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and growth of solid tumours. This study evaluated the expression of big endothelin-1 (big ET-1), a stable precursor of ET-1, and ET-1 in non-small cell lung cancer (NSCLC). Big ET-1 expression was evaluated in paraffin-embedded tissue sections from 10 NSCLC tumours using immunohistochemistry and in situ hybridisation. The production of big ET-1 and ET-1 was studied in six established NSCLC cell lines. The plasma concentrations of big ET-1 were measured in 30 patients with proven NSCLC prior to chemotherapy by means of a sandwich enzyme-linked immunoassay and compared to levels in 20 normal controls. Big ET-1 immunostaining was detected in the cancer cells of all tumours studied. Using in situ hybridisation, tumour cell big ET-1 mRNA expression was demonstrated in all samples. All six NSCLC cell lines expressed ET-1, with big ET-1 being detected in three. The median big ET-1 plasma level in patients with NSCLC was 5.4 pg/mL (range 0-22.7 pg/mL) and was significantly elevated compared to median big ET-1 plasma levels in controls, 2.1 pg/mL (1.2-13.4 pg/mL) (p = 0.0001). Furthermore, patients with plasma big ET-1 levels above the normal range (upper tertile) had a worse outcome (p = 0.01). In conclusion, big ET-1/ET-1 is expressed by resected NSCLC specimens and tumour cell lines. Plasma big ET-1 levels are elevated in NSCLC patients compared to controls with levels > 7.8 pg/mL being associated with a worse outcome. The development of selective ET-1 antagonists such as Atrasentan indicates that ET-1 may be a therapeutic target in NSCLC.
authors.affiliation: Department of Surgery , University Hospitals of Leicester NHS Trust, United Kingdom. sudhaarun@hotmail.com
authors.forename: C
authors.initials: C
authors.lastname: Arun
authors.forename: M
authors.initials: M
authors.lastname: DeCatris
authors.forename: D M
authors.initials: DM
authors.lastname: Hemingway
authors.forename: N J M
authors.initials: NJ
authors.lastname: London
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
mesh_terms: D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000378:metabolism*; D045744:Cell Line, Tumor; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000097:blood / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D019332:Endothelin-1; D012333:RNA, Messenger