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(American Journal of Pathology. 2002;161:183-193.)
© 2002 American Society for Investigative Pathology

Regular Articles

Transforming Growth Factor-ß1 Triggers Hepatocellular Carcinoma Invasiveness via {alpha}3ß1 Integrin

Gianluigi Giannelli*, Emilia Fransvea*, Felice Marinosci*, Carlo Bergamini*, Silvia Colucci{dagger}, Oronzo Schiraldi* and Salvatore Antonaci*

From the Department of Internal Medicine, Immunology, and Infectious Diseases,*Section of Internal Medicine, and the Department of Human Anatomy and Histology,{dagger}University of Bari Medical School, Bari, Italy

Metastasis occurrence in the course of hepatocellular carcinoma (HCC) severely affects prognosis and survival. We have shown that HCC invasive cells express {alpha}3ß1-integrin whereas noninvasive cells do not. Here we show that transforming growth factor (TGF)-ß1 stimulates {alpha}3-integrin expression at a transcriptional level in noninvasive HCC cells, causing transformation into a motile and invasive phenotype. Such activities are inhibited by neutralizing anti-{alpha}3- but not anti-{alpha}6-integrin monoclonal antibodies. HCC invasive cells secrete abundant levels of active TGF-ß1 in comparison with noninvasive cells, but in the latter, addition of active matrix metalloproteinases-2 increases the concentration of active TGF-ß1. In this way, the cells express {alpha}3-integrin at a transcriptional level and acquire motility on Ln-5. By contrast, an anti-TGF-ß1-neutralizing antibody reduces {alpha}3-integrin expression and the invasive ability of HCC invading cells. In HCC patients, TGF-ß1 serum concentrations and {alpha}3-integrin expression are strongly correlated. The integrin, absent in normal and peritumoral liver parenchyma, is abundantly expressed in HCC primary and metastatic tissue. In particular, patients with metastasis show higher levels of TGF-ß1 serum concentrations and stronger expression of TGF-ß1 and {alpha}3-integrin in HCC tissues. In conclusion, TGF-ß1 may play an important role in HCC invasiveness by stimulating {alpha}3-integrin expression, and could therefore be an important target for new therapies.


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