title: Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin.
abstract: Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte cross talk, we hypothesized that HSC-expressed endosialin might similarly affect cell proliferation during hepatocarcinogenesis. Indeed, the histological analysis of human HCC samples revealed an inverse correlation between tumor cell proliferation and stromal endosialin expression. Correspondingly, global genetic inactivation of endosialin resulted in accelerated tumor growth in an inducible mouse HCC model. A candidate-based screen of tumor lysates and differential protein arrays of cultured HSC identified several established hepatotropic cytokines, including IGF2, RBP4, DKK1, and CCL5 as being negatively regulated by endosialin. Taken together, the experiments identify endosialin-expressing HSC as a negative regulator of HCC progression.
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Institute of Pathology, Heidelberg University, Heidelberg, Germany.|Institute of Pathology, Technical University Munich, Munich, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Courtney
authors.initials: C
authors.lastname: König
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wieland
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Runge
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Besemfelder
authors.affiliation: Department of Medical Physics in Radiology, German Cancer Research Center Heidelberg, Heidelberg, Germany.
authors.forename: Dorde
authors.initials: D
authors.lastname: Komljenovic
authors.affiliation: Institute of Pathology, RWTH Aachen, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Institute of Pathology, Heidelberg University, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany augustin@angiogenese.de.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Hellmut G
authors.identifier: 0000-0002-7173-4242
authors.initials: HG
authors.lastname: Augustin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D000951:Antigens, Neoplasm / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C078203:CD248 protein, human; D009363:Neoplasm Proteins; C509258:tumor endothelial marker 1, mouse
keywords: 
  HCC
  ; cancer; stromal cross talk; tumor stroma; vascular biology