Abstract
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=10) 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±1.37pg/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) 30min 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. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Ali H, Loizidou M, Dashwood M, Savage F, Sheard C and Taylor I (2000a) Stimulation of colorectal cancer cell line growth by ET-1 and its inhibition by ETA antagonists. Gut 47: 685–688
Ali H, Dashwood M, Dawas K, Loizidou M, Savage F and Taylor I (2000b) Endothelin receptor expression in colorectal cancer. J Cardiovasc Pharm 36: S69–S71
Ashraf S, Loizidou M, Crowe R, Turmaine M, Burnstock G and Taylor I (1997) Blood vessels in liver metastases from both sarcoma and carcinoma lack perivascular innervation and smooth muscle cells. Clin Exp Metastasis 15: 484–498
Bagnato A, Tecce R, Dicastro V and Catt KJ (1997) Activation of mitogenic signalling by endothelin-1 in ovarian carcinoma cells. Cancer Res 57: 1306–1311
Bagnato A, Salani D, Di Castro V, Wu-Wong JR, Tecce R, Nicotra MR, Kenuti A and Natali PG (1999) Expression of ET-1 and ETA receptor in ovarian carcinoma: evidence for an autocrine tole in tumour growth. Cancer Res 59: 720–727
Clozel JP and Clozel M (1989) Effects of endothelin on the coronary vascular bed in open-chest dogs. Circ Res 65: 1193–1200
Clozel M, Gray GA, Breu V, Loffler BM and Osterwalder R (1992) The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 186: 867–873
Eberl LP, Valdenaire O, Saintgiorgio V, Jeannin J-F and Juillerat-Jeanneret L (2000) Endothelin receptor blockade potentiates FasL-induced apoptosis in rat colon carcinoma cells. Int J Cancer 86: 182–187
Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364
Hirata Y, Takagi Y, Fukuda Y and Marumi F (1989) Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 78s: 225–228
Inigagi H, Bishop AE, Eimoto T and Polak JM (1992) Autoradiographic localization of ET-1 binding sites in human colonic cancer tissue. J Pathol 168: 263–267
Kitigawa KN, Tsutsumi K, Niwa M, Yamaga S, Anda T and Khalid H (1994) A selective ETA antagonist, BQ123, inhibits 125I-ET-1 binding of human meningiomas and antagonizes ET-1 induced proliferation. Cell Mol Neurobiol 14: 105–118
Kojima K and Nihei Z (1995) Expression of ET-1 immunoreactivity in breast cancer. Surg Oncol 4: 309–315
Kusuhara M, Yamaguchi K, Ohnishi A, Abe K, Kimura S, Oono H, Hori S and Nakamura Y (1989) Endothelin potentiates growth factor stimulated DNA synthesis in Swiss 3T3 cells. Japn J Cancer Res 80: 302–305
Liu G, Henry KH Jr, Szczepankiewicz BG, Winn M, Kozmina NS, Boyd SA, Wasicak J, von Geldern TW, Wu-Wong JR, Chiou WJ, Dixon DG, Nguyen B, Marsh KC and Opgenorth TJ (1998) Pyrrolidine-3-carboxylic acids as endothelin antagonists. 3. Discovery of a potent 2-nonaryl, highly selective ETA antagonist (A-216546). J Med Chem 41: 3261–3275
Loesch A, Turmaine M, Loizidou M, Crowe R, Ashraf S, Taylor I and Burnstock G (1997) Increase in immunoreactivity for ET-1 in blood vessels of rat liver metastases: experimental sarcoma and carcinoma. J Anat 191: 291–299
Loizidou MC, Lawrance RJ, Holt S, Carty NJ, Cooper AJ, Alexander P and Taylor I (1991) Facilitation by partial hepatectomy of tumour growth within the rat liver following intraportal injection of syngeneic tumour cells. Clin Exp Metastasis 9: 335–349
Luttrell LM, Daaka Y and Lefkowitz J (1999) Regulation of tyrosine kinase cascades by G protein coupled receptors. Curr Opin Cell Biol 11: 177–183
Moraitis S, Langdon SP and Miller WR (1997) Endothelin expression and responsiveness in human ovarian cancer cell lines. Eur J Cancer 33: 661–668
Nakamuta M, Ohashi M, Tabata S, Tanabe Y, Goto K, Naruse M, Naruse K, Hiroshige K and Nawata H (1993) High plasma concentrations of ET-like immunoreactivities in patients with hepatocellular carcinoma. Am J Gastroenterol 88: 248–252
Nelson JB, Hedican SP, George DJ, Reddi AH, Piantadosi S, Eisenberger MA and Simon JW (1995) Identification of ET-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1: 944–949
Nelson JB, Chan-Tack K, Hedican SP, Magnuson SR, Opgenorth TJ, Bova GS and Simons JW (1996) Endothelin-1 production and decreased ETB receptor expression in advanced prostatic cancer. Cancer Res 56: 663–668
Oikawa T, Kushuhara M, Ishikawa S, Hitomi J, Kono A, Iwanaga T and Yamaguchi K (1994) Production of ET-1 and thrombomodulin by human pancreatic cancer cells. Br J Cancer 69: 1059–1064
Ong A, Jowett T, Scoble J, O'shea P, Varghese Z and Moorhead J (1993) Effect of cyclosporin A on endothelin synthesis by cultured human renal cortical epithelial cells. Nephrol Dial Transplant 8: 748–753
Shankar A, Loizidou M and Taylor I (1996) The vascularity of colorectal liver metastases. Eur J Surg Oncol 22: 389–396
Shankar A, Loizidou M, Aliev G, Fredericks S, Holt D, Boulos PB, Burnstock B and Taylor I (1998) Raised ET-1 levels in patients with colorectal liver metastases. Br J Surg 85: 502–506
Shichiri M, Hirata Y, Nakajima T, Ando K, Imai T, Yanagisawa M, Masaki T and Marumo F (1991) Endothelin-1 is an autocrine/paracrine growth factor for human cancer cell lines. J Clin Invest 87: 1867–1871
Shichiri M, Marumo F and Yukio H (1998) Endothelin-B receptor-mediated supression of endothelial apoptosis. J Cardiovasc Pharmacol 31: S138–S141
Simonson MS, Wamm S, Mene P, Dubyak GR, Kester M, Nakazato Y, Sedor JR and Dunn MJ (1989) Endothelin stimulated phospholipase C, Na+/H+ exchange c-fos expression and mitogenesis in rat mesanglial cells. J Clin Invest 83: 708–712
Simpson RA, Dickinson T, Porter KE, London NJM and Hemingway DM (2000) Raised levels of plasma Big ET-1 in patients with colorectal cancer. Br J Surg 87: 1409–1413
Sutanto-Ward E, Sigurdson ER, Tremiterra S, Lincer R, Chapman D and Niedzwiecki D (1992) Adjuvant chemotherapy for colorectal hepatic metastases: role of route of administration and timing. Surg Oncol 1: 87–95
Wilson J, Hunt SJ, Tang E, Wright N, Kelly E, Palmer S, Heys C, Mellor S, James R and Bialecki R (1999) Pharmacological profile of 2D1611, an orally active ETA antagonist. J Pharmacol Exp Ther 290: 1085–1091
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K and Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415
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Asham, E., Shankar, A., Loizidou, M. et al. Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ETA receptor antagonism. Br J Cancer 85, 1759–1763 (2001). https://doi.org/10.1054/bjoc.2001.2193
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DOI: https://doi.org/10.1054/bjoc.2001.2193
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