Expression of the ghrelin/growth hormone secretagogue receptor axis and its functional role in promoting tumor growth in primary central nervous system lymphomas.

Ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), have been found in a variety of malignant tumor tissues, suggesting a biological function of the ghrelin/GHS-R axis in tumor growth and progression. Among central nervous system tumors, primary central nervous system lymphomas (PCNSLs) are relatively rare and characterized by a rapid progression and poor prognosis. In order to clarify ghrelin expression and its functional role in promoting tumor growth and progression in PCNSLs, we undertook an immunohistochemical investigation for ghrelin and GHS-R expression in 43 patients and tested the effect of ghrelin inhibition on lymphoma cells. Furthermore, we investigated the expression of CD105, a marker for tumor angiogenesis, to explore its association with the ghrelin/GHS-R axis. The Kaplan-Meier method and Cox's proportional hazards regression model were used to determine the association of ghrelin/GHS-R expression with overall survival rate. The immunohistochemical study showed moderate/strong immunostaining of cells for ghrelin and GHS-R in 40 patients (93.0%) and 39 patients (90.7%), respectively. A ghrelin inhibitor did not affect tumor cell proliferation in vitro. Expression levels of ghrelin and GHS-R were divided into high and low groups by the rate of moderate-strong staining cells to tumor cells. The survival rate was significantly lower in patients with high GHS-R expression (P = 0.0368 by log-rank test; P = 0.0219 by Wilcoxon test). In addition, multivariate analysis of overall survival using Cox's proportional hazards regression model indicated that GHS-R was a significant independent prognostic factor (P = 0.0426). CD105 expression on tumor vessels was positive in 33 patients (33/37, 89.2%). There was a positive correlation between the moderate-strong staining rate of ghrelin and CD105-positive vessel count. These results indicated that the ghrelin/GHS-R axis plays a potential role in promoting tumor growth and progression through neoangiogenesis, rather than the proliferation of tumor cells.