Characterization of the differential efficacy of somatostatin receptor agonists in the inhibition of the growth of experimental gliomas and identification of the intracellular mechanisms involved

Somatostatin (SST) exerts antiproliferative effects in normal and tumor epithelial and endocrine cells through the activation of five G protein-coupled receptors (SSTR15). Somatostatin receptors are expressed in several human tumors, including brain cancer. Multiple intracellular pathways are involved in the antiproliferative effects of SST, both direct (cytostatic, pro-apoptotic) and indirect (antiangiogenic, antiendocrine). In particular, modulation of phosphotyrosine phosphatase (PTP) h activity is considered as a major mechanism in SST regulation of cell growth. Among brain cancers, malignant gliomas are aggressive, infiltrating, and highly vascularized lesions characterized by poor prognosis. The highly tumorigenic rat glioma C6 cell line natively expressing SSTR1, 2, 3, and 5, is a reliable experimental model for the study of glioma growth and neoangiogenesis. As tumor cells express multiple SSTRs, it is essential to deepen the individual role of the different subtypes in the regulation of cell proliferation and intracellular pathways. In C6 cells, in vitro and in vivo, SST and SSTR1, 2, and 5 selective agonists act as cytostatic agents via PTPh-dependent inhibition of ERK1/2 activity and upregulation of p27kip1. SSTR1, 2, and 5 activation leads to tumor growth inhibition acting on both cell proliferation and neoangiogenesis. Somatostatin receptor 5 activation showed the highest efficacy, although the combined activity of different SSTR subtypes resulted in additive effects. The present review summarizes the cytostatic activity of SST and presents novel insights into the individual role of SSTR, bringing this knowledge into perspective for the future use of SSTRs as molecular targets for antiproliferative strategies.