Animal Modeling of Pediatric Liver Cancer

Abstract

Hepatoblastoma (HB) is the most common pediatric liver malignancy. Management of HB requires multidisciplinary efforts. The 5-year overall survival of this disease is about 80% in developed countries. Despite advances in the care of these patients, survival in recurrent or treatment-refractory disease is lower than 50%. This is due to more complex tumor biology, including hepatocellular carcinoma (HCC)-like mutations and expression of aggressive gene signatures leading to chemoresistance, vascular invasion, and metastatic spread. The current treatment protocols for pediatric liver cancer do not incorporate targeted therapies, and the ability to test these therapies is limited due to the inaccessibility of cell lines and mouse models. In this review, we discuss the current status of preclinical animal modeling in pediatric liver cancer, primarily HB. Although HB is a rare cancer, the research community has worked together to develop a range of interesting and relevant mouse models for diverse preclinical studies.

Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model

“…Previous approaches have been applied to establish hepatoblastoma models, including xenograft implantation [92][93][94][95][96][97][98][99][100] , generation of transgenic mice 28,48,101 and hydrodynamic tail vein injection of oncogenes 22,24 , and each of these models has its pros and cons 34 . Additionally, most of these models develop the well-differentiated fetal type of hepatoblastoma, which usually has a good clinical outcome even without chemotherapy administration 102 .…”

“…Due to a lack of targetable somatic mutations and paucity of genetic animal disease models and cell lines 33,34 , identi cation of therapeutic targets in hepatoblastoma remains challenging. Conventional chemotherapy is critical for most hepatoblastoma treatment.…”

Bridging molecular basis, prognosis, and treatment of pediatric liver tumors

“…Integrative analysis of transcriptomic and methylomic data of metastasized and non-metastasized HB samples identified the Sp8 transcription factor (SP8) as a highly upregulated gene in metastatic tumors [59] . Interestingly, HB patients with high SP8 expression levels were also prognostic for poor survival.…”

“…SP8mediated aggressive traits such as cell motility and clonogenic growth could be abrogated in SP8-silenced cell models using RNA interference. Of clinical relevance, application of the FDA-approved pan SP transcription factor mithramycin A abolished SP8-induced effects [59] .…”

Genetically Engineered Mouse Models of Liver Tumorigenesis Reveal a Wide Histological Spectrum of Neoplastic and Non-Neoplastic Liver Lesions

“…This is particularly problematic for the scientific community, because the use of generally accepted pathology nomenclature for unexpected and novel findings leads to publications that can be interpreted by readers, including other pathologists [11]. Additionally, this is important, since histopathological phenotypes in GEMM can be very tricky to diagnose, specifically in the liver "tumor" setting, mirroring the situation in human liver pathology [12][13][14][15][16][17][18]. Additionally, although a histopathological classification of animal proliferative (and non-proliferative) liver lesions exists [19], these definitions, provided by the Society of (Veterinarian) Toxicopathology, are unknown to broad parts of the scientific community.…”