Hepatoblastoma: current knowledge and promises from preclinical studies

Abstract

The survival rate for patients with metastatic hepatoblastoma (HB) is steadily increased in the last thirty years from 27% to 79%. These achievements result from accurate risk stratification and effective chemotherapy and surgical care. However, patients with poor prognosis require more effective therapies. Recent years have witnessed new insights on the biology of HB, setting the stage for molecular classification and new targets of therapy. We review here the molecular pathology of HB, focusing on the driver genes involved in the process of oncogenesis and the identification of novel targets. We also address the role of in vivo models in elucidating the mechanisms of development of this disease and the pre-clinical phase of new treatment modalities.

Keywords: Hepatoblastoma (HB); Yap; mTORC1; therapeutic strategies; β-catenin.

Figure 1

Histological subtypes of human HB. (A) Pure fetal HB showing the organization in trabeculae of the tumor. Tumor cells resemble fetal hepatocytes and show a large cytoplasm, which appears either clear/white or pink due to the different content of glycogen and lipids of the tumor cells. This peculiar “light and dark pattern” is better appreciable at higher magnification in (B); (C) mixed fetal-embryonal HB, characterized by the presence of two distinct population of cells. While fetal tumor cells (*) display a pink and large cytoplasm, embryonal HB cells (arrows) show prominent, highly basophilic nuclei, a small cytoplasm, and a high nuclear/cytoplasmic ratio; (D) often, embryonal-like HB cells tend to form rosettes (“pseudo-rosettes”), acini or tubules, exhibiting a pseudoglandular phenotype; (E) examples of a SCU HB. SCU cells have minimal cytoplasm and round lightly chromatic nuclei. Different from embryonal-like cells, SCU cells do not form tubules, pseudo-glands or any other organized structure; (F) part of a mixed epithelial-mesenchymal HB containing osteoid as a mesenchymal component. Original magnification: 100× in C; 200× in A; 400× in B, D, E, and F. Hematoxylin and eosin staining was employed. HB, hepatoblastoma; SCU, small cell undifferentiated.

Figure 2

Strategy of treatment according to risk.

Figure 3

Scheme depicting the cooperation between Yap and β-catenin protooncogenes in hepatoblastoma development. Activation of Yap and β-catenin results in transcriptional programs in association with TEAD4 and TCF proteins, respectively. In addition, both protooncogenes are able to induce the mTORC1, a major modulator of cellular functions. Of note, mTORC1 can be specifically inhibited (as indicated by red, blunted arrows) by Rapamycin and its homologs (Rapalogs, such as Everolimus and Sirolimus). Thus, mTORC1 inhibition might represent a potentially relevant therapy for this disease. mTORC1, mammalian target of rapamycin complex 1.