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Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma
Author(s) -
Lin Nan,
Chen Zhiju,
Lu Yi,
Li Yangzhu,
Hu Kunpeng,
Xu Ruiyun
Publication year - 2015
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12356
Subject(s) - hepatic stellate cell , angiogenesis , metastasis , stromal cell , cancer research , cd34 , hepatocellular carcinoma , in vivo , vascular endothelial growth factor , pathology , tumor microenvironment , in vitro , medicine , cancer , biology , stem cell , microbiology and biotechnology , vegf receptors , tumor cells , biochemistry
Aim Cancer is not only influenced by specific tumor cells but also by the stromal microenvironment. Upon liver damage, activated hepatic stellate cells ( aHSC ) become highly proliferative myofibroblast‐like cells and are thought to secrete molecules that influence development of hepatocellular carcinoma ( HCC ). The aim of this study was to investigate the role of aHSC in the development of HCC . Methods To assess if aHSC secreted factor(s) that promote microvascular endothelial cell ( MEC ) tube formation, MEC were plated with aHSC ‐conditioned medium and tube formation analyzed by light microscopy. An established transendothelial migration assay with MEC was used to evaluate the role of aHSC in migration and metastasis. A novel in vitro and in vivo orthotopic mouse HCC tumor model was used to investigate angiogenic, proliferative and metastatic activity of aHSC . Results We found that aHSC promoted angiogenesis both in vitro and in vivo through vascular endothelial growth factor ( VEGF ). aHSC ‐conditioned medium increased the ability of MEC to form tubes which was dependent upon aHSC ‐secreted VEGF . In addition, HCC orthogenic tumors derived from co‐injection of H22 cells plus aHSC into the hepatic lobes of mice had greater cell proliferation and vascularization, as evaluated by the presence of CD34 and VEGF expression, than tumors resulting from H22 injections alone. aHSC also migrated from the primary tumor to sites of metastasis. Conclusion Our findings support aHSC playing multiple roles in HCC development and metastasis.