Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas

Wnt/beta-catenin signaling is frequently activated in cancer cells by stabi lizing mutations of beta-catenin or loss-of-function mutations of the APC t umor suppressor gene. We have analysed the role of beta-catenin in the path ogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2 -terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3 beta phosphorylation motif or interstitial deletions in 12 tum ors (67%), In the remaining cases, no truncating mutation of APC could be e videnced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrat ed nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated ce lls, Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover , are show that beta-catenin is aberrantly overexpressed in a large spectru m of tumor components, including hepatocyte-like cells at various different iation stages and heterologous elements such as squamous, osteoid and chron droid tissues, and in occasional other mesenchymally-derived cells. These d ata strongly suggest that activation of beta-catenin signaling is an obliga tory step in HE pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early sta ges of hepatic differentiation.