Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma.
Liver cirrhosis is the main risk factor for the development of hepatocellular carcinoma (HCC). Activated hepatic stellate cells (HSC) are the effector cells of hepatic fibrosis and also infiltrate the HCC stroma where they might play a critical role in HCC progression. Here we aimed to analyze the effects of activated HSC on the proliferation and growth of HCC cell lines in vitro and in vivo. Conditioned media (CM) collected from HSC significantly induced proliferation and migration of HCC cells cultured in monolayers. In a 3-dimensional spheroid coculture system, HSC promoted HCC growth and diminished the extent of central necrosis. In accordance, in vivo simultaneous implantation of HSC and HCC cells into nude mice promoted tumor growth and invasiveness, and inhibited necrosis formation. As potential mechanism of the tumorigenic effects of HSC we identified activation of NFkappaB and extracellular-regulated kinase (ERK) in HCC cells, two signaling cascades that play a crucial role in HCC progression. In summary, our data indicate that stromal HSC promotes HCC progression and suggest the HSC-HCC interaction as an interesting tumor differentiation-independent target for therapy of this highly aggressive cancer.
Amann
Thomas
T
Department of Internal Medicine I, University of Regensburg, D-93053, Regensburg, Germany.
Bataille
Frauke
F
Spruss
Thilo
T
Mühlbauer
Marcus
M
Gäbele
Erwin
E
Schölmerich
Jürgen
J
Kiefer
Paul
P
Bosserhoff
Anja-Katrin
AK
Hellerbrand
Claus
C
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004789:Enzyme Activation; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D017077:Culture Media, Conditioned; D016328:NF-kappa B; D020933:Neurotrophin 3; D012333:RNA, Messenger; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3