Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612770
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

Dynamic communication patterns determine the endothelial cell rheostat in liver capillarization and tumorigenesis

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

Publication History

Publication Date:
03 January 2018 (online)

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Background:

The composition of the liver endothelial network consisting of liver sinusoidal- and capillary endothelial cells (LSECs and CECs) is strictly maintained by paracine-acting feedback loops. In many liver diseases including carcinogenesis, the disturbed spatiotemporal communication between LSECs and CECs is leading to a massive CEC expansion (called capillarization). The underlying molecular mechanisms leading to the reorganization of the endothelial cell network are however still unclear.

Results:

To investigate the dynamic communication patterns of endothelial cells (ECs) in premalignant and malignant livers, comprehensive transcriptome analysis of primary isolated CECs (CD31, CD146, Lyve-1-) and LSECs (CD31, CD146, Lyve-1) derived from YAPS127A-transgenic mice was performed. Bioinformatic analysis revealed the differential expression of paracrine-acting pathway constituents including BMP2/BMPR, SDF1/Cxcr4, VEGFC/VEGFR3 and of HGF/c-MET in CECs and LSECs. The dynamic behavior of the LSEC/CEC crosstalk was illustrated for the HGF/c-MET axis showing an exclusive induction of c-MET on CECs in the step-wise development of liver cancer, while LSEC-derived HGF levels remained unchanged. In vitro the promigratory effect of HGF was confirmed with the endothelial cell line SVEC 4 – 10 using single cell tracking-based time-lapse microscopy and spheroid sprouting. In vivo the inhibition of the HGF/c-MET crosstalk between LSECs and CECs by the c-MET inhibitor Cabozantinib (Cabometyx®) led to reduced CEC sprouting associated with reduced tumor cell proliferation (Ki67).

In order to identify tumor-derived factors, which may initiate the dynamic crosstalk between LSECs and CECs, proteome profiling of blood samples derived from control and YAPS127A mice was performed. Among the identified secreted factors, Osteopontin (OPN) was regulated in a YAP/TEAD-dependent manner in primary hepatocytes (ChIP). Indeed, application of recombinant OPN on SVEC 4 – 10 cells led to an induction of c-MET and CD146. The prognostic relevance of CEC markers as well as of OPN was confirmed in a cohort of HCC patients (Roessler et al. 2010).

Conclusion:

Our results illustrate for the first time a dynamic crosstalk between the two major EC populations in the process of liver disease and tumor development. This interaction is already detectable in early phases of capillarization and is induced by tumor-cell-derived factors such as OPN. Since the HGF/c-MET axis represents an essential signal pathway in the process of arterial branch elongation, early inhibition through clinically relevant c-MET inhibitors may represent a promising approach to disease-associated capillarization.