Production of Endothelin in Human Cancer Cell Lines

Endothelin (ET)-1 is a vasoconstrictor peptide derived from endothelial cells and now known to be a local regulator of vascular tonus. Recent studies, however, have revealed that ET-1 functions also as growth factor in various cells. By using a specific ET-1 radioimmunoassay, immunore-active (IR) ET-1, ranging from 4.2 to 150 pM (minimum detectable amount, 4.0 pM), was detected in 13 of 42 human cancer cell lines. The frequencies of IR-ET-1 production and its concentrations were high in mammary, pancreatic, and colon carcinoma cell lines. IR-ET-1 produced by cancer cells possessed the same molecular size as synthetic ET-1 and also had ET-1-like biological activity. Moreover, Northern blot analysis revealed bands corresponding to ET-1 mRNA in cancer cell lines, indicating that IR-ET-1 produced by cancer cells is a product of the ET-1 gene. Since ET-1 in the spent media is present in a sufficient amount to stimulate cellular growth, we sought ET-1 receptors in four pancreatic carcinoma cell lines and human skin fibroblasts. No ET-1 receptors were detected in the pancreatic carcinoma cell lines. However, human skin fibroblasts possessed a large number of ET-1 receptors. This finding raises the possibility that ET-1 produced by cancer cells plays a modulatory role in the growth of stromal cells surrounding cancer cells.