Somatostatin Receptors in Human Neuroendocrine Tumors

Abstract

Somatostatin is a peptide with potent and broad antisecretory action and an invaluable drug target for the pharmacological management of neuroendocrine tumors (NETs). For the diagnosis and therapy of NETs, somatostatin analogs (SSAs) have been used in clinic for many years. Five somatostatin receptors (SSTRs) have been identified. Molecular mechanisms of SSTR signaling and regulation have refined our understanding of the SSTR biology, their expression in NETs, agonist-specific regulation of receptor signaling, internalization, and phosphorylation, especially for SSTR 2, which is the primary target of current somatostatin analog therapy for NETs. The expression of SSTRs on NET cells forms the basis for SSA treatment of patients with SSTR-positive, hormonally active NETs. In patients with SSTR-negative ETs, the clinical response to SSAs is generally absent or suboptimal, while nonfunctioning NETs with SSTR positivity show a variable response to such therapy. In an IHC-based analysis of SSTR subtypes in hepatic metastases and primary neuroendocrine carcinomas (NECs) of small intestine and pancreas, we found expression to be heterogeneous among different tumors and within individual tumors. In the hepatic metastatic tissues from small intestinal and pancreatic NECs, the prevalence of SSTR 2 expression was 81 and 72 %, respectively. Most importantly, we found an obvious evidence of heterogeneity of expression of the various SSTR subtypes in the primary entero-pancreatic NECs and their hepatic metastases. In order to maximize clinical benefit of SSA therapies to NET/NEC patients, SSTR-subtype expression needs to be standardized and systematically correlated with the imaging and clinical results of SSA therapy. With an improved understanding of SSTR pharmacology, we can hope to aid the future development of SSAs with increased efficacy. Investigating the function of each SSTR in various NETs will provide the rationale for developing multi-receptor-targeted SSA therapies, also in combination with other targeted agents like mTOR.