Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene, that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named 'metastin'. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.

Galanin is a widely distributed neuropeptide with a variety of physiological functions. Three galanin receptor subtypes, GALR1, GALR2, and GALR3, have been reported. We isolated a novel galanin-like peptide (GALP) from porcine hypothalamus by observing its activity for increasing [35 S]GTP␥S binding to a membrane preparation of GALR2-transfected cells. The peptide had 60 amino acid residues and a non-amidated C terminus. The amino acid sequence of GALP-(9 -21) was completely identical to that of galanin-(1-13). A cloned porcine GALP cDNA indicated that GALP was processed from a 120-amino acid GALP precursor protein. The structures of rat and human GALP-(1-60) were deduced from cloned cDNA, which indicated that the amino acid sequences 1-24 and 41-53 were highly conserved between humans, rats, and pigs. Receptor binding studies revealed that porcine GALP-(1-60) had a high affinity for the GALR2 receptor (IC 50 ‫؍‬ 0.24 nM) and a lower affinity for the GALR1 receptor (IC 50 ‫؍‬ 4.3 nM). In contrast, galanin showed high affinity for the GALR1 (IC 50 ‫؍‬ 0.097 nM) and GALR2 receptors (IC 50 ‫؍‬ 0.48 nM). GALP is therefore an endogenous ligand that preferentially binds the GALR2 receptor, whereas galanin is relatively non-selective.Galanin, a C-terminally amidated peptide with 29 amino acid residues (non-amidated peptide with 30 residues in humans) was originally isolated from porcine intestine (1) and was later found to be ubiquitous in the central and peripheral nervous systems. It exerts diverse regulatory functions including central modulation of cognition, nociception, and feeding behavior, endocrine control of pituitary and pancreatic hormones, and regulation of gastrointestinal smooth muscle contractions (for review, see Refs. 2, 3).Structurally, galanin is unrelated to any known family of neuropeptides or regulatory peptides, suggesting the presence of unknown members of a galanin peptide family. Indeed, the existence of a galanin-like peptide(s) in mammalian tissues has been proposed for several reasons. First, molecular heterogeneity of galanin-like immunoreactivity has been reported by several groups. Rökaeus et al. (4) first reported that rat brain and ileum contained galanin-like peptides that cross-reacted with galanin antiserum but differed from galanin in chromatographic characterization. Nevertheless, some of these immunoreactivities may be the result of galanin precursors or galaninderived peptides, as described in the subsequent studies (5). Recently, Wang et al. (6) re-evaluated the existence of a novel galanin-like peptide in rat islets by showing the presence of galanin-like immunoreactivity that cross-reacted with antibody against porcine galanin but did not with antibody against rat galanin. Second, the physiological function of the three galanin receptor subtypes, GALR1 1 (7, 8), GALR2 (9, 10), and GALR3 (11,12), is unlikely to be solely the distribution of different signals to target cells. The low affinity of human galanin for human GALR3 (12) suggests the possibility that these receptor s...

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