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SHR Neuro Cancer Cardio Lipid Metab Microb

Svejda, B; Kidd, M; Timberlake, A; Harry, K; Kazberouk, A; Schimmack, S; Lawrence, B; Pfragner, R; Modlin, IM.
Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors.
Cancer Sci. 2013; 104(7):844-855 Doi: 10.1111/cas.12174 [OPEN ACCESS]
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Co-authors Med Uni Graz: Pfragner Roswitha
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Abstract:: 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-HT₇ receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5-HT₇ receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5-HT-mediated signaling pathways (pCREB, 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-HT₇ expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5-HT₇ receptor. 5-HT activated cAMP/PKA activity, pCREB (130-205%, P < 0.05) and pERK/pAKT (1.2-1.75, P < 0.05). Signaling was reversed by the 5-HT₇ receptor antagonist SB269970. IGF-1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC₅₀: 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-HT₇ was increased fourfold compared to sham-operated animals. We conclude that hepatocytes express a cAMP-coupled 5-HT₇ 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-HT₇ in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine-producing mid-gut tumors.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Cell Line, Tumor -; Cell Proliferation -; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Hepatocytes - metabolism; Insulin-Like Growth Factor I - metabolism; Intestinal Neoplasms - metabolism; Intestine, Small - metabolism; Liver Neoplasms - metabolism; MAP Kinase Signaling System -; Mice -; Mice, SCID -; Neuroendocrine Tumors - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats -; Receptors, Serotonin - metabolism; Serotonin - metabolism; Signal Transduction - physiology; Tumor Microenvironment - physiology