title: Physical supports from liver cancer cells are essential for differentiation and remodeling of endothelial cells in a HepG2-HUVEC co-culture model.
abstract: Blood vessel remodeling is crucial in tumor growth. Growth factors released by tumor cells and endothelium-extracellular matrix interactions are highlighted in tumor angiogenesis, however the physical tumor-endothelium interactions are highly neglected. Here, we report that the physical supports from hepatocellular carcinoma, HepG2 cells, are essential for the differentiation and remodeling of endothelial cells. In a HepG2-HUVEC co-culture model, endothelial cells in direct contact with HepG2 cells could differentiate and form tubular structures similar to those plated on matrigel. By employing HepG2 cell sheet as a supportive layer, endothelial cells formed protrusions and sprouts above it. In separate experiments, fixed HepG2 cells could stimulate endothelial cells differentiation while the conditioned media could not, indicating that physical interactions between tumor and endothelial cells were indispensable. To further investigate the endothelium-remodeling mechanisms, the co-culture model was treated with inhibitors targeting different angiogenic signaling pathways. Inhibitors targeting focal adhesions effectively inhibited the differentiation of endothelial cells, while the growth factor receptor inhibitor displayed little effect. In conclusion, the co-culture model has provided evidences of the essential role of cancer cells in the differentiation and remodeling of endothelial cells, and is a potential platform for the discovery of new anti-angiogenic agents for liver cancer therapy.
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Geraldine Giap Ying
authors.initials: GGY
authors.lastname: Chiew
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Afu
authors.initials: A
authors.lastname: Fu
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Kar
authors.initials: K
authors.lastname: Perng Low
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
authors.forename: Kathy
authors.initials: K
authors.lastname: Qian Luo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques / Q000379:methods; D003094:Collagen / Q000008:administration & dosage; D017077:Culture Media, Conditioned / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007797:Laminin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D011509:Proteoglycans / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A
chemical_list: D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen