Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ETA receptor antagonism

被引:105
作者
Asham, E
Shankar, A
Loizidou, M
Fredericks, S
Miller, K
Boulos, PB
Burnstock, G
Taylor, I
机构
[1] UCL Royal Free & Univ Coll, Sch Med, Dept Surg, London W1W 7EJ, England
[2] UCL Royal Free & Univ Coll, Sch Med, Dept Histopathol, London W1W 7EJ, England
[3] UCL Royal Free & Univ Coll, Sch Med, Auton Neurosci Inst, London NW3 2PF, England
[4] Univ London St Georges Hosp, Sch Med, Analyt Unit, London SW17 0QT, England
关键词
ET-1; colorectal cancer; colorectal liver metastases; ETA antagonist; ETB; antagonist; BQ123;
D O I
10.1054/bjoc.2001.2193
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Endothelin-1 (ET-1) is a vasoconstrictor peptide which stimulates proliferation in vitro in different cell types, including colorectal cancer cells. Raised ET-1 levels have been detected both on tissue specimens and in the plasma of patients with cancers. To investigate the role of ET-1 in colorectal cancer: (i) ET-1 plasma levels in patients with colorectal cancer were measured by radioimmunoassay: group 1 = controls (n = 22), group 2 = primary colorectal cancer only (n = 39), group 3 = liver metastases only (n = 26); (ii) ET-1 expression in primary colorectal cancer specimens (n =1 0) was determined immunohistochemically and (iii) the effect of intraportally infused antagonists to the two ET-1 receptors, ETA and ETB, on the growth of liver metastases in a rat model was assessed. ET-1 plasma levels were significantly increased in both patients with primary tumour and patients with metastases, compared to controls (P < 0.01, 3.9 +/- 1.4, 4.5 +/- 1.5, vs. 2.75 +/- 1.37 pg/ml, respectively). Immunohistochemically, strong expression of ET-1 was found in the cytoplasm, stroma and blood vessels of cancers, unlike the normal colon where only the apical layer of the epithelium, vascular endothelial cells and surrounding stroma were positively stained. In the rat model, there was significant reduction in liver tumour weights compared to controls, following treatment with the ETA antagonist (BQ123) 30 min after the intraportal inoculation of tumour cells (P < 0.05). These results suggest ET-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ETA receptors. ETA antagonists are indicated as potential anti-cancer agents. (C) 2001 Cancer Research Campaign.
引用
收藏
页码:1759 / 1763
页数:5
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