Liver cancer stemness and metastasis

Hepatocellular carcinoma (HCC) correlate with poor survival of patients due to delayed diagnosis and frequent recurrence after adjuvant treatment. The majority of malignant hepatic lesions shows a tremendous heterogeneity in differentiation patterns and molecular signatures which challenges efficient therapeutic intervention. In this project we tackle the differentiation of neoplastic hepatocytes and its consequences on HCC progression, including the crucial involvement of putative liver cancer stem cells. We propose to assess the neoplastic differentiation repertoire and liver tumor stem cell repository by employing established hepatocytes lacking p19ARF . These immortalized / non-tumorigenic p19ARF null hepatocytes reconstitute damaged livers after transplantation by generating bi-potent hepatic progenitor cells, and after malignant transformation, adopt a metastatic phenotype through the synergy of hyperactive Ras and transforming growth factor (TGF)-beta signaling. Our recent data indicate that the malignant progression of these hepatocytes is associated with the (i) differentiation into a phenotype comparable with hepatic myofibroblasts, (ii) TGF-beta dependent activation of platelet-derived growth factor (PDGF) and beta-catenin signaling as well as (iii) overt expression of stem cell markers. These insights into the epithelial plasticity of neoplastic hepatocytes suggest a link between the hallmarks of HCC and hepatic cancer stemness. In a transplantation model of liver tumor progression we propose to investigate the diversity of differentiation patterns of malignant hepatocytes that occur at the inner area of the tumor versus the tumor-host interface and distal metastases. In particuar, we address the question whether the differentiation of hepatocytes and the gain of stem cell markers is a prerequisite of tumor cell dissemination. Serial analysis of tumor cell recovery and orthotopic retransplantation will allow to study the progression of neoplastic cell types and to discriminate between non- metastatic and metastatic malignant hepatocytes, the latter considered as putative hepatic cancer stem cells. To complement studies at the molecular level, we will analyze TGF-beta / PDGF and beta-catenin signaling linked to hepatic tumor stem cell properties. These studies will facilitate the determination of the hepatic cancer (stem) cell fate and its underlying molecular mechanisms, which is of particular relevance for the design of novel effective protocols in HCC therapy.

Hepatocellular carcinoma (HCC) correlate with poor survival of patients due to delayed diagnosis and frequent recurrence after adjuvant treatment. The majority of malignant hepatic lesions shows a tremendous heterogeneity in differentiation patterns and molecular signatures which challenges efficient therapeutic intervention. In this project we tackle the differentiation of neoplastic hepatocytes and its consequences on HCC progression, including the crucial involvement of putative liver cancer stem cells. We propose to assess the neoplastic differentiation repertoire and liver tumor stem cell repository by employing established hepatocytes lacking p19ARF . These immortalized / non-tumorigenic p19ARF null hepatocytes reconstitute damaged livers after transplantation by generating bi-potent hepatic progenitor cells, and after malignant transformation, adopt a metastatic phenotype through the synergy of hyperactive Ras and transforming growth factor (TGF)-beta signaling. Our recent data indicate that the malignant progression of these hepatocytes is associated with the (i) differentiation into a phenotype comparable with hepatic myofibroblasts, (ii) TGF-beta dependent activation of platelet-derived growth factor (PDGF) and beta-catenin signaling as well as (iii) overt expression of stem cell markers. These insights into the epithelial plasticity of neoplastic hepatocytes suggest a link between the hallmarks of HCC and hepatic cancer stemness. In a transplantation model of liver tumor progression we propose to investigate the diversity of differentiation patterns of malignant hepatocytes that occur at the inner area of the tumor versus the tumor-host interface and distal metastases. In particuar, we address the question whether the differentiation of hepatocytes and the gain of stem cell markers is a prerequisite of tumor cell dissemination. Serial analysis of tumor cell recovery and orthotopic retransplantation will allow to study the progression of neoplastic cell types and to discriminate between non- metastatic and metastatic malignant hepatocytes, the latter considered as putative hepatic cancer stem cells. To complement studies at the molecular level, we will analyze TGF-beta / PDGF and beta-catenin signaling linked to hepatic tumor stem cell properties. These studies will facilitate the determination of the hepatic cancer (stem) cell fate and its underlying molecular mechanisms, which is of particular relevance for the design of novel effective protocols in HCC therapy.