Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597470
4. Tumors/Liver Surgery
Georg Thieme Verlag KG Stuttgart · New York

Distinct transcriptome and secretome patterns characterize capillarization in early and late phases of hepatocarcinogenesis

S Thomann
1   University of Heidelberg, Institute of Pathology, Heidelberg, Germany
,
S Marquard
1   University of Heidelberg, Institute of Pathology, Heidelberg, Germany
,
S Weiler
1   University of Heidelberg, Institute of Pathology, Heidelberg, Germany
,
M Dittmer
2   University of Heidelberg, Department of Parasitology, Heidelberg, Germany
,
S Roessler
1   University of Heidelberg, Institute of Pathology, Heidelberg, Germany
,
C Sticht
3   of Heidelberg, Medical Faculty Mannheim, Center of Medical Research, Mannheim, Germany
,
N Gretz
3   of Heidelberg, Medical Faculty Mannheim, Center of Medical Research, Mannheim, Germany
,
C Mogler
4   Technical University of Munich, Institute of Pathology, Munich, Germany
,
C Ball
5   DKFZ, National Center for Tumor Diseases (NCT), Heidelberg, Germany
,
H Glimm
5   DKFZ, National Center for Tumor Diseases (NCT), Heidelberg, Germany
,
E Ryschich
6   University of Heidelberg, Section for Surgical Research, Heidelberg, Germany
,
P Schirmacher
1   University of Heidelberg, Institute of Pathology, Heidelberg, Germany
,
K Breuhahn
1   University of Heidelberg, Institute of Pathology, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

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Background: In chronic liver diseases and hepatocarcinogenesis capillary endothelial cells (CECs) gradually change the liver-specific microcirculation by replacing liver sinusoidal endothelial cells (LSECs). This process of capillarization impairs the hepatic function and is caused by micro-environmental changes such as hepatocyte secretome alterations. However, the impact of tumor-derived, secreted factors on capillarization as well as a comparative morphological, biochemical and molecular characterization of the involved endothelial cell types in different stages of hepatcarcinogenesis is missing.

Results: The capillarization reaction was analyzed in transgenic mice with inducible and liver-specific expression of the constitutively active oncogene yes-associated protein (YAPS127A; Tschaharganeh et al. 2013). Immunofluorescence of Lyve-1 and CD146 revealed a progressive replacement of LSECs by CECs in livers, hyperplastic/premalignant lesions, and hepatocellular carcinomas (HCCs). FACS analysis of primary isolated endothelial cells confirmed the selective expansion of CECs with 4 ± 2% in normal liver, 37 ± 16% in hyperplastic livers, and 61 ± 30% in tumor-bearing livers. Expression profiling analysis of primary isolated LSECs and CECs from normal livers, premalignant lesions, and tumor-bearing livers identified stage- and cell type-specific molecular patterns including cytokine/chemokine signatures. To identify paracrine effector pathways regulating capillarization in tumorigenesis, proteome profiling of supernatants derived from primary hepatocyte- and YAPS127A-induced tumor cells was performed. Several proangiogenic factors were induced in tumor cells including the placental growth factor (PGF) and tissue inhibitor of metalloproteinase 1 (TIMP1), illustrating an oncogene-dependent paracrine effect on endothelial cells. Analysis of human HCC gene expression data from 242 HCC patients confirmed the prognostic relevance of the identified proangiogenic factors (Roessler et al. 2010).

Conclusion: Capillarization is a specific event in hepatocarcinogenesis characterized by distinct molecular traits. Dynamic changes of the hepatocellular secretome occur early in liver tumor development and its perturbation might represent a possible approach for an early inhibition of tumor-supporting capillarization.