title: Effect of adipocyte-secreted factors on EpCAM+/CD133+ hepatic stem cell population.
abstract: Recent epidemiological studies have associated obesity with a variety of cancer types including HCC. However, the tumor initiating role of obesity in hepatocarcinogenesis is still unknown. The objective of this paper is to investigate the effect of adipocyte-secreted factors on EpCAM+/CD133+ cancer stem cells and to identify which factors play a role in modulating hepatic cancer stem cell behavior. Our results demonstrated that adipocyte-secreted factors affect motility and drug resistance of EpCAM+/CD133+ cells. When incubated with adipocyte conditioned media, EpCAM+/CD133+ cells exhibited augmented motility and reduced sorafenib-induced apoptosis. Using array-based system, we identified secretion of several cytokines such as IL6, IL8 and MCP1 by cultured adipocytes and activation of c-Met, STAT3 and ERK1/2 signaling pathways in EpCAM+/CD133+ cells incubated with adipocyte conditioned media. Treating EpCAM+/CD133+ cancer stem cells with IL6 receptor blocking antibody or c-Met inhibitor SU11274 both reduced the increase in motility; however SU11274 had greater effect on relieving protection from sorafenib-induced apoptosis. These results indicate that adipocyte-secreted factors might regulate cancer stem cell behavior through several signaling molecules including c-Met, STAT3 and ERK1/2 and inhibition of these signaling pathways offer novel strategies in targeting the effect of adipose-derived cytokines in cancer.
authors.affiliation: Faculty of Engineering and Computer Science, Izmir University of Economics, Izmir, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Firtina Karagonlar
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Doğukan
authors.initials: D
authors.lastname: Koç
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Eren
authors.initials: E
authors.lastname: Şahin
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Sanem Tercan
authors.initials: ST
authors.lastname: Avci
authors.affiliation: Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Yilmaz
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Neşe
authors.initials: N
authors.lastname: Atabey
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey. Electronic address: esra.erdal@deu.edu.tr.
authors.forename: Esra
authors.initials: E
authors.lastname: Erdal
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D000071916:AC133 Antigen; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C000606023:PROM1 protein, human
keywords: Adipocytes; Cytokines; HCC; IL6; STAT3; c-Met