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Critical Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Anchorage-independent Growth and Hematogeneous Intrahepatic Metastasis of Liver Cancer¹

Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045 [K. N., M. S., J. Y., M. T., S. H.]; Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 [N. F., T. T.]; Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 113-0032 [T. T.]; and Department of General Surgery, Hokkaido University, Graduate School of Medicine, Sapporo 060-8638 [K. N., S. T.], Japan

In the multistep process of metastasis, "anchorage-independent growth," where cancer cells need to survive without cell-substratum interaction, is supposed to be important. In this study, we found that anchorage-independent growth analyzed using the soft agar colony formation assay correlated with hematogeneous intrahepatic metastasis of liver cancer cell lines and also Akt activation status. Two highly metastatic liver cancer cell lines showed high Akt activity and formed many colonies in soft agar, whereas three nonmetastatic cell lines showed less Akt activity and formed fewer colonies. Inhibition of Akt activation in the highly metastatic cell line Li7 by transfection with kinase-dead Akt or the phosphatidylinositol 3-kinase inhibitor, LY294002, resulted in formation of fewer colonies in soft agar than was the case with control cells. Moreover, in orthotopic implantation model, this inhibition resulted in a reduced rate of hematogeneous intrahepatic metastasis. These findings indicated that anchorage-independent growth regulated by phosphatidylinositol 3-kinase/Akt pathway plays a critical role in metastasis, and that this could be a potential therapeutic target to combat metastasis.

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