Activated HSCs (hepatic stellate cells) are the main source of extracellular matrix proteins present in cirrhotic liver on which HCC (hepatocellular carcinoma) commonly develops. HCC cells behave differently according to differences in the surrounding microenvironment. In the present study, we have investigated a mechanism whereby HSCs modulate the migratory activity of HCC cells. We used primary cultures of human HSCs to investigate their effect on Hep3B, Alexander, HLE and HLF HCC cells. The expression of Ln-5 (laminin-5) was documented at transcript and protein levels both in vitro and in vivo. HCC cells strongly adhere, migrate and spread in the presence of HSC-conditioned medium and of co-culture. HSCs produce and secrete Ln-5 in the CM (conditioned medium). The electrophoretic pattern of secreted Ln-5 is consistent with that of a migratory substrate, showing the presence of the γ2x fragment. Blocking antibodies against Ln-5 inhibit HCC migration in the presence of HSC-CM. HCC cells migrate very poorly in the presence of Ln-5 immunodepleted HSC-CM. HCC migration in the presence of HSCs is dependent on the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathway, but not the PI3K (phosphoinositide 3-kinase)/Akt pathway. HSC-CM, as well as Ln-5, activates the MEK/ERK but not the PI3K/Akt pathway. In human HCC tissues, Ln-5 is mainly distributed along α-SMA (smooth muscle actin)-positive cells, whereas in peritumoural tissues, Ln-5 is absent. HSCs stimulate HCC migration via the production and secretion of Ln-5.
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Research Article|
April 28 2011
Hepatic stellate cells stimulate HCC cell migration via laminin-5 production
Angela Santamato;
Angela Santamato
*Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
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Emilia Fransvea;
Emilia Fransvea
*Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
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Francesco Dituri;
Francesco Dituri
*Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
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Alessandra Caligiuri;
Alessandra Caligiuri
†Department of Internal Medicine, University of Florence Medical School, Florence, Italy
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Michele Quaranta;
Michele Quaranta
‡Department of Experimental Oncology, Laboratory of Analyses, National Cancer Institute, Bari, Italy
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Tomoaki Niimi;
Tomoaki Niimi
§Laboratory of Industrial Biosciences, Department of Bioengineering Sciences, Nagoya University, Nagoya, Japan
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Massimo Pinzani;
Massimo Pinzani
†Department of Internal Medicine, University of Florence Medical School, Florence, Italy
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Salvatore Antonaci;
Salvatore Antonaci
*Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
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Gianluigi Giannelli
*Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy
Correspondence: Associate Professor Gianluigi Giannelli (email g.giannelli@intmed.uniba.it).
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Publisher: Portland Press Ltd
Received:
January 07 2011
Revision Received:
March 11 2011
Accepted:
March 18 2011
Accepted Manuscript online:
March 18 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2011 Biochemical Society
2011
Clin Sci (Lond) (2011) 121 (4): 159–168.
Article history
Received:
January 07 2011
Revision Received:
March 11 2011
Accepted:
March 18 2011
Accepted Manuscript online:
March 18 2011
Citation
Angela Santamato, Emilia Fransvea, Francesco Dituri, Alessandra Caligiuri, Michele Quaranta, Tomoaki Niimi, Massimo Pinzani, Salvatore Antonaci, Gianluigi Giannelli; Hepatic stellate cells stimulate HCC cell migration via laminin-5 production. Clin Sci (Lond) 1 August 2011; 121 (4): 159–168. doi: https://doi.org/10.1042/CS20110002
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