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We hypothesized that 5\u2010HT<\/jats:styled-content> produced by metastatic EC<\/jats:styled-content> cells played a role in the hepatic tumor\u2010microenvironment principally via 5\u2010HT<\/jats:styled-content>7<\/jats:sub> receptor\u2010mediated activation of hepatocyte IGF<\/jats:styled-content>\u20101 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5\u2010HT7<\/jats:sub> receptor expression (using PCR<\/jats:styled-content>, sequencing and western blot). ELISA<\/jats:styled-content>, cell transfection and western blots delineated 5\u2010HT<\/jats:styled-content>\u2010mediated signaling pathways (pCREB<\/jats:styled-content>, AKT<\/jats:styled-content> and ERK<\/jats:styled-content>). IGF<\/jats:styled-content>\u20101 synthesis\/secretion was evaluated using QPCR<\/jats:styled-content> and ELISA<\/jats:styled-content>. IGF<\/jats:styled-content>\u20101 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF<\/jats:styled-content>\u20101 production and 5\u2010HT<\/jats:styled-content>7<\/jats:sub> expression were examined in an in vivo <\/jats:italic>SCID<\/jats:styled-content> metastasis model. Our results demonstrated evidence for a functional 5\u2010HT<\/jats:styled-content>7<\/jats:sub> receptor. 5\u2010HT<\/jats:styled-content> activated cAMP<\/jats:styled-content>\/PKA<\/jats:styled-content> activity, pCREB<\/jats:styled-content> (130\u2013205%, P\u00a0<\/jats:italic><\u00a0<\/jats:italic>0.05) and pERK<\/jats:styled-content>\/pAKT<\/jats:styled-content> (1.2\u20131.75, P\u00a0<\/jats:italic><\u00a0<\/jats:italic>0.05). Signaling was reversed by the 5\u2010HT7<\/jats:sub> receptor antagonist SB269970. IGF<\/jats:styled-content>\u20101 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC50<\/jats:sub>: 7\u201370\u00a0pg\/mL) and could be reversed by the small molecule inhibitor BMS<\/jats:styled-content>\u2010754807. IGF<\/jats:styled-content>\u20101 and 5\u2010HT<\/jats:styled-content> were elevated (40\u2013300\u00d7) in peri\u2010tumoral hepatic tissue in nude mice, while 5\u2010HT<\/jats:styled-content>7<\/jats:sub> was increased fourfold compared to sham\u2010operated animals. We conclude that hepatocytes express a cAMP<\/jats:styled-content>\u2010coupled 5\u2010HT7<\/jats:sub> receptor, which, at elevated 5\u2010HT concentrations that occur in liver metastases, signals via CREB<\/jats:styled-content>\/AKT<\/jats:styled-content> and is linked to IGF<\/jats:styled-content>\u20101 synthesis and secretion. Because IGF<\/jats:styled-content>\u20101 regulates NEN<\/jats:styled-content> proliferation, identification of a role for 5\u2010HT<\/jats:styled-content>7<\/jats:sub> in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine\u2010producing mid\u2010gut tumors.<\/jats:p>","DOI":"10.1111\/cas.12174","type":"journal-article","created":{"date-parts":[[2013,4,11]],"date-time":"2013-04-11T15:18:51Z","timestamp":1365693531000},"page":"844-855","source":"Crossref","is-referenced-by-count":43,"title":["Serotonin and the 5\u2010HT<\/scp>7 receptor: The link between hepatocytes, IGF<\/scp>\u20101 and small intestinal neuroendocrine tumors"],"prefix":"10.1111","volume":"104","author":[{"given":"Bernhard","family":"Svejda","sequence":"first","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Kidd","sequence":"additional","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Timberlake","sequence":"additional","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Harry","sequence":"additional","affiliation":[{"name":"Yale Liver Center Yale University School of Medicine New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kazberouk","sequence":"additional","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Schimmack","sequence":"additional","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roswitha","family":"Pfragner","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology and Immunology Center for Molecular Medicine Medical University of Graz Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irvin M.","family":"Modlin","sequence":"additional","affiliation":[{"name":"Gastrointestinal Pathobiology Research Group Yale University School of Medicine New Haven Connecticut; USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,5,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0110"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02175-9"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.3.674"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/335254a0"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1999.276.6.F922"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101824200"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.01.006"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2006.12.003"},{"key":"e_1_2_6_10_1","first-page":"99","article-title":"Hepatic microvascular regulatory mechanisms. 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