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Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

¹ Department of Medicine, Texas A&M Health Science Center, College of Medicine, Scott & White Hospital; ² Systems Biology and Translational Medicine, Texas A&M University System Health Science Center, College of Medicine; ³ Division of Research, Central Texas Veterans Health Care System; ⁴ Texas Biosciences Institute, Temple College, Temple, Texas; ⁵ Department of Internal Medicine, Instituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy; ⁶ Division of Anatomy, University "La Sapienza," Rome, Italy; ⁷ Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; ⁸ Department of Clinical Medicine, Division of Gastroenterology, University of Rome "La Sapienza" Polo Pontino, Latina, Italy; ⁹ Department of Medicine, University of Washington, Seattle, Washington; and ¹⁰ Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy

Requests for reprints: Sharon DeMorrow, Department of Internal Medicine, Scott and White Hospital and Texas A&M Health Science Center, Medical Research Building, 702 SW H.K. Dodgen Loop, Temple, TX 76504. Phone: 254-724-6240; Fax: 254-724-8070; E-mail: demorrow{at}medicine.tamhsc.edu.

Key Words: monoamine oxidase A • tryptophan hydroxylase • xenograft

Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines, compared with normal cholangiocytes, and tissue and bile from cholangiocarcinoma patients. Specifically, there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin, respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represent the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies. [Cancer Res 2008;68(22):9184–93]