Serotonin and the 5‐ HT 7 receptor: The link between hepatocytes, IGF ‐1 and small intestinal neuroendocrine tumors

Platelet‐derived serotonin (5‐ HT ) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin ( EC ) cell “carcinoid” (neuroendocrine) neoplasms, the principal cellular source of 5‐ HT . We hypothesized that 5‐ HT produced by metastatic EC cells played a role in the hepatic tumor‐microenvironment principally via 5‐ HT 7 receptor‐mediated activation of hepatocyte IGF ‐1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5‐HT 7 receptor expression (using PCR , sequencing and western blot). ELISA , cell transfection and western blots delineated 5‐ HT ‐mediated signaling pathways (p CREB , AKT and ERK ). IGF ‐1 synthesis/secretion was evaluated using QPCR and ELISA . IGF ‐1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF ‐1 production and 5‐ HT 7 expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5‐ HT 7 receptor. 5‐ HT activated c AMP / PKA activity, p CREB (130–205%, P < 0.05) and p ERK /p AKT (1.2–1.75, P < 0.05). Signaling was reversed by the 5‐HT 7 receptor antagonist SB269970. IGF ‐1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC 50 : 7–70 pg/mL) and could be reversed by the small molecule inhibitor BMS ‐754807. IGF ‐1 and 5‐ HT were elevated (40–300×) in peri‐tumoral hepatic tissue in nude mice, while 5‐ HT 7 was increased fourfold compared to sham‐operated animals. We conclude that hepatocytes express a c AMP ‐coupled 5‐HT 7 receptor, which, at elevated 5‐HT concentrations that occur in liver metastases, signals via CREB / AKT and is linked to IGF ‐1 synthesis and secretion. Because IGF ‐1 regulates NEN proliferation, identification of a role for 5‐ HT 7 in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine‐producing mid‐gut tumors.