title: Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma.
abstract: Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1-mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550-61. ©2016 AACR.
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Benita
authors.initials: B
authors.lastname: Wolf
authors.affiliation: Department for Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Krieg
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Falk
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Keppeler
authors.affiliation: FACS Core Facility of the Interdisciplinary Center for Clinical Research of the University Hospital of Tuebingen, University of Tuebingen, Tuebingen, Germany. Department of Dermatology and Allergy Biederstein, Technical University Munich, Munich, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Biedermann
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Schmid
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Warmann
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Fuchs
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vetter
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Tuebingen, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Thiele
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Tuebingen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Nieser
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Meltem
authors.initials: M
authors.lastname: Avci-Adali
authors.affiliation: Division of Translational Oncology, Department of Hematology, Immunology, University Hospital Tuebingen.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Skokowa
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany. Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hauser
authors.affiliation: Second Medical Department, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Virology, Technische Universität München (TUM)/Helmholtz Zentrum München (HMGU), Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ringelhan
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yevsa
authors.affiliation: Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Virology, Technische Universität München (TUM)/Helmholtz Zentrum München (HMGU), Munich, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany. Department for Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany. uta.kossatz-boehlert@med.uni-tuebingen.de.
authors.forename: Uta
authors.initials: U
authors.lastname: Kossatz-Boehlert
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000378:metabolism*; D044842:Cullin Proteins; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008113:Liver Neoplasms / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D016133:Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D054360:Chemokine CXCL1; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; C475895:Cxcl1 protein, mouse; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases