ABSTRACT
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in these cancers. Several recent studies estimate that ITH is inherent to HCC and attribute the clinical intractability of HCC to this heterogeneity. In this review, we examine the evidence for genomic, phenotypic, and tumor microenvironment ITH in HCC, with a focus on two of the top molecular drivers of HCC: ß-catenin (CTNNB1) and Telomerase reverse transcriptase (TERT). We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy, while highlighting the gaps in knowledge and possible future directions.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Hepatocellular , Immune Checkpoint Inhibitors/pharmacology , Liver Neoplasms , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Antineoplastic Agents, Immunological/pharmacology , Biomarkers, Pharmacological/analysis , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/pathology , Clinical Trials as Topic , Drug Monitoring/methods , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Progression-Free SurvivalABSTRACT
The assays in this study utilize mouse embryonic stem cells (mESCs) and zebrafish embryos to evaluate the potential developmental toxicity of industrial and pharmaceutical chemicals. A set of eleven chemicals of known mammalian in vivo teratogenicity were tested in the assays and correlations to mammalian data. Using mESCs, proliferation, differentiation, and cytotoxicity of the chemicals were measured. In zebrafish embryos, lethality and the lowest effect level concentrations for morphological malformations were determined. Clustering of the assays based on frequency of affected assays resulted in a ranking of the test compounds that correlated to in vivo rodent data (R = 0.88, P < 0.001). We conclude that the combination of ESC- and zebrafish-based assays provides a valuable platform for the prioritization of pharmaceutical and industrial chemicals for further testing of developmental toxicity in rodents.
Subject(s)
Embryo, Nonmammalian/drug effects , Mouse Embryonic Stem Cells/drug effects , Teratogens/toxicity , Toxicity Tests/methods , Zebrafish/abnormalities , Animals , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Embryo, Nonmammalian/abnormalities , MiceABSTRACT
The Liver X Receptors (LXRs) play important roles in multiple metabolic pathways, including fatty acid, cholesterol, carbohydrate and energy metabolism. To expand the knowledge of the functions of LXR signaling during embryonic development, we performed a whole-genome microarray analysis of Lxr target genes in zebrafish larvae treated with either one of the synthetic LXR ligands T0901317 or GW3965. Assessment of the biological processes enriched by differentially expressed genes revealed a prime role for Lxr in regulating lipid metabolic processes, similarly to the function of LXR in mammals. In addition, exposure to the Lxr ligands induced changes in expression of genes in the neural retina and lens of the zebrafish eye, including the photoreceptor guanylate cyclase activators and lens gamma crystallins, suggesting a potential novel role for Lxr in modulating the transcription of genes associated with visual function in zebrafish. The regulation of expression of metabolic genes was phenotypically reflected in an increased absorption of yolk in the zebrafish larvae, and changes in the expression of genes involved in visual perception were associated with morphological alterations in the retina and lens of the developing zebrafish eye. The regulation of expression of both lipid metabolic and eye specific genes was sustained in 1 month old fish. The transcriptional networks demonstrated several conserved effects of LXR activation between zebrafish and mammals, and also identified potential novel functions of Lxr, supporting zebrafish as a promising model for investigating the role of Lxr during development.
Subject(s)
Lipid Metabolism , Orphan Nuclear Receptors/metabolism , Visual Perception/genetics , Zebrafish/growth & development , Animals , Benzoates/pharmacology , Benzylamines/pharmacology , Cell Line , Gene Expression Profiling , Gene Expression Regulation, Developmental/drug effects , Hydrocarbons, Fluorinated/pharmacology , Lens, Crystalline/drug effects , Lens, Crystalline/metabolism , Lipid Metabolism/drug effects , Liver X Receptors , Oligonucleotide Array Sequence Analysis , Orphan Nuclear Receptors/genetics , Retinal Neurons/drug effects , Retinal Neurons/metabolism , Sulfonamides/pharmacology , Visual Perception/drug effects , Zebrafish/geneticsABSTRACT
Environmental factors affecting nutrient availability during development can cause predisposition to diseases later in life. To identify chemicals in the environment capable of altering nutrient mobilization, we analyzed yolk malabsorption in the zebrafish embryo, which relies on maternally-derived yolk for nutrition during its first week of life. Embryos of the transgenic zebrafish line HGn50D, which fluoresce in the yolk syncytial layer, were exposed from two to five days post fertilization to different chemicals. We developed a software package to automatically and accurately segment and quantify the area of the fluorescing yolk in images captured at the end of the treatment period. Based on this quantification, we found that prochloraz decreased yolk absorption, while butralin, tetrabromobisphenol A, tetrachlorobisphenol A and tributyltin increased yolk absorption. Given the number and variety of industrial chemicals in commerce today, development of automated image processing to perform high-speed quantitative analysis of biological effects is an important step for enabling high throughput screening to identify chemicals altering nutrient absorption.
