Signaling of ghrelin and its functional receptor, the growth hormone secretagogue receptor, promote tumor growth in glioblastomas

Ghrelin is a 28‐amino‐acid peptide that is the endogenous ligand for the pituitary growth hormone secretagogue receptor (GHS‐R). Ghrelin is mainly produced from the stomach, but it is also expressed by various other tissues, including the CNS under normal conditions. Physiologically, ghrelin regulates appetite, gut motility, and GH release from the anterior pituitary, as well as cardiovascular and immune systems. Recent studies also indicate that ghrelin and GHS‐R may play an important autocrine/paracrine role in neoplastic conditions. In order to clarify the role of ghrelin/GHS‐R in gliomas, the present study assessed the expression of ghrelin and its functional receptor, GHS‐R1a, in 39 glioblastomas (GBs), 13 anaplastic astrocytomas (AAs) and 11 diffuse astrocytomas (DAs) using immunohistochemical analyses. Immunohistochemical staining was evaluated as follows: no staining; 1+, 0–10% positive cells; 2+, 10–50% positive cells; 3+, >50% positive cells. Ghrelin expression was detected in 52 of 63 cases of which 38, 13 and one were scored as 3+, 2+ and 1+, respectively. GHS‐R1a expression was detected in 45 of 63 cases of which 29, 15 and one were scored as 3+, 2+ and 1+, respectively. Ghrelin immunoreactivity was observed in 38 of 39 GBs, 12 of 13 AAs and two of 11 DAs. GHS‐R1a immunoreactivity was observed in 39 of 39 GBs, five of 13 AAs, and one of 11 DAs. AAs and GBs showed moderate or strong immunostaining of ghrelin/GHS‐R1a in the tumor cells and in proliferating microvessels. Patients were classified into lower to moderate‐score, and high‐score ghrelin/GHS‐R categories according to the principal component and cluster analyses. Multivariate analysis of overall survival indicated that there was a significant difference (P = 0.0001) in the survival rate between these two groups. The combined results indicated that expression of the ghrelin/GHS‐R1a axis increases the growth of AAs and GBs through an autocrine/paracrine mechanism.