Altered endothelin receptor subtypes in colorectal cancer.
BACKGROUND
The vasoactive peptide endothelin-1 (ET-1) acts via two endothelin receptor subtypes, ETA (ETAR) and ETB (ETBR). ET-1 and ETAR are overexpressed in colorectal cancer tissues. In vitro, ET-1 acting via ETAR, is a mitogen for colorectal cancer cells. To identify other potential stimulatory loops, we investigated the distribution and cell-specific localization of both ETAR and ETBR in tissue sections from patients with colorectal cancer.


METHODS
Frozen sections from specimens of colorectal cancer (n=9) and normal colon (n=9) were cut and subjected to either (i) autoradiography or (ii) a combination of cell type-specific immunohistochemistry, using antibodies against fibroblasts (AS02), endothelial cells (CD31) or nerve fibres (NF200) and in-vitro receptor microautoradiography, using ETAR-specific and ETBR-specific radioligands.


RESULTS
ETARs were upregulated in all cell types, apart from nerve, in cancer compared with normal colon (1:1.59 normal to cancer). Specifically, ETAR binding was highest in cancer-associated blood vessels and fibroblasts and to a lesser extent in epithelial cancer cells. In contrast, ETBRs were the predominant receptors in normal colon (1:0.59 normal to cancer) and were markedly down-regulated in cancer-associated blood vessels, fibroblasts and to a lesser extent in epithelial cells. Nerve colocalization was demonstrated, but remained unchanged for all tissues.


CONCLUSIONS
The shift in ET receptor binding observed in epithelial cancer cells and cancer-associated fibroblasts and endothelial cells may favour ET-1 signals contributing to colorectal cancer growth and neovascularization via ETAR. This may provide the basis for therapeutic use of specific ETAR antagonists as adjuvant treatment of colorectal cancer.
Hoosein
Moinuddin M
MM
Department of Surgery, Royal Free and University College Medical School, London, UK.
Dashwood
Michael R
MR
Dawas
Khaled
K
Ali
Haythem M M D A
HM
Grant
Katherine
K
Savage
Felicity
F
Taylor
Irving
I
Loizidou
Marilena
M
D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D015854:Up-Regulation
D019332:Endothelin-1; D009363:Neoplasm Proteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B