Tumor-endothelial cell interaction in an experimental model of human hepatocellular carcinoma

Exp Cell Res. 2018 Nov 1;372(1):16-24. doi: 10.1016/j.yexcr.2018.09.001. Epub 2018 Sep 8.


Hepatocellular carcinoma (HCC) is a densely vascularized tumor that is highly dependent on angiogenic pathways to direct arterial blood flow to the growing neoplasm, though little is known about how the interaction of tumor and endothelial cells drives these processes and the degree of clinical importance. To this end, we examined the intercellular cross-talk between HepG2 (human HCC) and human endothelial progenitor cells (EPC) in a co-culture system that mimics some aspects of initial tumor parenchyma and stroma interactions. The results showed that the remote cell-to-cell (paracrine) interactions between HepG2 cells and EPC play a critical role in the differentiation and angiogenic activity of endothelial cells, possibly through intercellular signaling function of the exosomes released in the medium by HepG2 cells. The tumor-cell activated phenotype of EPC was associated with increased migration and elevated expression of ephrin-B2, and Delta-like 4 ligand (DLL4). Furthermore, ephrin-B2 was found to be overexpressed in HCC and cholangiocarcinoma tissue samples taken from humans. Overall, our results demonstrate that ephrin-B2 and Dll4 mediated co-dependence of HCC and EPC intercellular crosstalk in the initial stages of HCC establishment and development, a promising target for new clinical strategies.

Keywords: Angiogenesis; EPC; Exosomes; HCC; Tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Death
  • Cell Movement
  • Coculture Techniques
  • Collagen / chemistry
  • Culture Media, Conditioned / chemistry
  • Culture Media, Conditioned / pharmacology
  • Culture Media, Serum-Free / chemistry
  • Diffusion Chambers, Culture
  • Drug Combinations
  • Endothelial Progenitor Cells / cytology
  • Endothelial Progenitor Cells / drug effects
  • Endothelial Progenitor Cells / metabolism*
  • Ephrin-B2 / genetics
  • Ephrin-B2 / metabolism*
  • Exosomes / chemistry
  • Exosomes / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Laminin / chemistry
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Models, Biological*
  • Paracrine Communication / genetics*
  • Proteoglycans / chemistry
  • Signal Transduction
  • Tumor Microenvironment


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • Culture Media, Conditioned
  • Culture Media, Serum-Free
  • DLL4 protein, human
  • Drug Combinations
  • EFNB2 protein, human
  • Ephrin-B2
  • Intercellular Signaling Peptides and Proteins
  • Laminin
  • Proteoglycans
  • matrigel
  • Collagen