Endocrine Abstracts

Neuroendocrine tumor cells express a diverse array of activating and inhibitory receptors. Each receptor transduces a signal via individual pathways which often interact or overlap. Common stimulatory receptor families include those for EGF/TGFα, FGF, IGF, PDGF, VEGF, and TGFβ. EGF receptor (Her 1) activation results in several signal transduction cascades including Ras/Raf, MAPK, AKT and JNK leading to DNA synthesis and cell proliferation. Activated MAPK signaling is a common feature of GEP-NETs (‘carcinoids’), but the absence of activating mutations in the EGF receptor suggests this is not due to EGF/TGFα. The four FGF receptors combine to create 48 isoforms; the predominant isoforms FGFR1–4 are expressed in all GEP-NETs; signaling activation is associated with mitogenesis and differentiation as well as cross-talk within the tumor microenvironment (endothelial cell activation). IGF1R is present in the majority (>70%) of GEP-NETs and is coupled to Ras/Raf, MAPK and the PI3K–AKT–mTOR pathway. IGF1R activation is associated with survival and proliferation in mitosis-competent cells (e.g. serotonin-mediated hepatocyte-production of IGFs by hepatic metastases) and hypertrophy in differentiated cells. PGFRs are occasionally expressed in GEP-NETs and are associated with MAPK/AKT activation. The majority of expression, however, occurs in tumor stroma, and is associated with angiogenesis. The VEGFR has also been identified in GEP-NETs, and the production of VEGF by NETs is coupled to endothelial cell mitogenesis/migration and angiogenesis. TGFβRs are present in the majority (~90%) of GEP-NETs. In pancreatic NETs, they are coupled to the classical SMAD2/3 pathway and inhibition of proliferation. In contrast, in small intestinal NETs, TGFβR are coupled to SMAD4/7 which results in tumor proliferation via cross-activation of MAPK and AKT. Common inhibitory receptor families include those for TGFβ, interferon, somatostatin, dopamine and serotonin. Somatostatin receptors are coupled to PKA/cAMP and calcium channels and activation inhibits cell secretion. There is some evidence that proliferation may be diminished but the mechanisms have not been clearly delineated. Dopamine D2/D4 receptors activation may inhibit NET function, largely via cAMP inhibition, although there is considerable heterogeneity in dopamine receptor expression in tumors (D2 as well as stimulatory D1,3,5 – which activate PKA/cAMP). Interferons activate IFNGR1/2 and signal through JAK/STAT pathways leading to apoptosis. Certain subtypes of small intestinal NETs express serotonin receptors, usually 5-HT_2A/B. Activation of these receptors inhibit serotonin secretion and cell proliferation via inhibition of MAPK signaling. Many NETs also exhibit loss of the G1 checkpoint inhibitor P21^WAF1/CIP1. Other potential signaling pathways include hedgehog (SHH – over-expressed in metastases) and NOTCH (potentially involved with secretion). In conclusion, the expression of a variety of receptors activating diverse transduction events that enable stimulation or inhibition of tumor growth provide a number of opportunities for therapeutic intervention that might target growth, secretion or angiogenesis.