Gastrin releasing peptide-preferring bombesin receptors mediate growth of human renal cell carcinoma

Bombesin-like peptides typically act as neurotransmitters along the brain-g ut axis and as growth factors in various human tissues. The present study d emonstrates the expression of gastrin releasing peptide (GRP)-preferring bo mbesin receptors in human renal cell carcinoma but not in normal kidney tis sue. The expression of GRP receptors was characterized at the mRNA level by reverse transcription-PCR, as well as at the protein level by binding of I -125-[Tyr(4)] bombesin to membranes prepared from tumor tissue (K-d 0.3 nM) and healthy kidney tissue from the same four patients. GRP receptors were also demonstrated in four human kidney carcinoma cell lines (A-498, CAKI-1, CAKI-2, and ACHN). The effects of bombesin/GRP agonists and/or antagonists on growth were investigated in vitro on CAKI-2 cells, which expressed larg e amounts of GRP receptors. Cell numbers stimulated by 10% fetal calf serum were significantly stimulated by interleukin-1 beta (control) and GRP-7 (1 0(-7) M), both in the range of 136 to 148%; addition of the GRP receptor an tagonist acetyl-GRP(20-27) (10(-6) M) completely reversed this effect. Bomb esin alone (10(-6) M) significantly stimulated CAKI-2 cells (129%) cultured with 0.5% fetal calf serum, whereas another antagonist, D-Phe6,Leu13,(CH2N H)Leu14 bombesin(6-14) (1 mu M), alone did not inhibit growth, thus excludi ng an autocrine mechanism. These results indicate for the first time that m alignant transformation of human kidney tissue into renal cell carcinoma is accompanied by novel expression of GRP receptors. Bombesin-like peptides m ight act as mitogens in these carcinomas, and they might be useful as diagn ostic or therapeutic tools such as tumor imaging or internal radiotherapy.