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Leptin Enhances Cholangiocarcinoma Cell Growth

Departments of ¹ Gastroenterology and ² Pathology, Università Politecnica delle Marche, Ancona, Italy; ³ Division of Research, Central Texas Veterans Health Care System, ⁴ Department of Medicine, and ⁵ Systems Biology and Translational Medicine, and ⁶ Division Research and Education, Scott and White Hospital, Texas A & M Health Science Center College of Medicine, Temple, Texas; and ⁷ Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy, and Polo Pontino, Latina, Italy

Requests for reprints: Giammarco Fava, Department of Gastroenterology Università Politecnica delle Marche Nuovo Polo Didattico, III piano via Tronto 10 60020, Ancona, Italy. Phone: 39-0712206043; Fax: 39-0712206044; E-mail: giammarcofava{at}hotmail.com.

Key Words: leptin • cholangiocarcinoma • proliferation • tumor • hormone • thioacetamide • obesity • cholangiopathies

Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3–dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of cholangiocarcinoma. [Cancer Res 2008;68(16):6752–61]