Web-based access to mouse models of human cancers: the Mouse Tumor Biology (MTB) Database

The Mouse Tumor Biology (MTB) Database serves as a curated, integrated resource for information about tumor genetics and pathology in genetically defined strains of mice (i.e., inbred, transgenic and targeted mutation strains). Sources of information for the database include the published scientific literature and direct data submissions by the scientific community. Researchers access MTB using Web-based query forms and can use the database to answer such questions as 'What tumors have been reported in transgenic mice created on a C57BL/6J background?', 'What tumors in mice are associated with mutations in the Trp53 gene?' and 'What pathology images are available for tumors of the mammary gland regardless of genetic background?'. MTB has been available on the Web since 1998 from the Mouse Genome Informatics web site (http://www.informatics.jax.org). We have recently implemented a number of enhancements to MTB including new query options, redesigned query forms and results pages for pathology and genetic data, and the addition of an electronic data submission and annotation tool for pathology data.     

Mouse models of human diseases.

Cancer, poliomyelitis, Alzheimer's and Gaucher disease, a seemingly disparate array of disorders, have become the target of powerful genetic analysis and drug screening protocols, using mouse strains that have been genetically altered to serve as models for understanding the disease and for helping the patient.     

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM)

Objectives

In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions.

Introduction

All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. in Omics 15:173–182, 2011; Fan et al. in Metabolomics 7(2):257–269, 2011a, in Pharmacol Ther 133:366–391, 2012a, in Metabolomics 8(3):517–527, b; Xie et al. in Cell Metab 19:795–809, 2014; Ren et al. in Sci Rep 4:5414, 2014; Sellers et al. in J Clin Investig 125(2):687–698, 2015). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by Warburg (Biochem Z 142:317–333, 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014). As the microenvironment of the target human tissue is retained and individual patient’s response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical trials or treatments

Conclusions

Development of ex vivo human tissue and animal models with humanized organs including bone marrow and liver show considerable promise for analyzing drug responses that are more relevant to humans. Similarly using stable isotope tracer methods with these improved models in advanced stages of the drug development pipeline, in conjunction with tissue biopsy is expected significantly to reduce the high failure rate of experimental drugs in Phase II and III clinical trials.

     

Mouse models for human DNA mismatch-repair gene defects

The mammalian DNA mismatch-repair genes belong to a family of genes that comprise several homologs of the Escherichia coli mutS and mutL genes. The observation that mutations in the two human repair genes MSH2 and MLH1 are responsible for hereditary nonpolyposis colorectal cancer, as well as a significant number of sporadic colorectal cancers, raises several questions about the role of these proteins and their family members in the initiation and progression of colorectal cancer. To address these questions, mice with inactivating mutations in all the known mutS and mutL homologs have been generated. The development of these mouse lines has permitted the systematic analysis of the role of each gene in the repair process and has underscored their significance in mutation avoidance and cancer susceptibility. These analyses were critical for our understanding of the function of these genes at the organismal level and also revealed an essential role for some of the DNA mismatch-repair genes in mammalian meiosis.     

Mouse Hepatitis Virus (MHV-2)

Various factor sinfluencing the plaque formation of mouse hepatitis virus (MHV-2) in DBT cell monolayers were studied and a practical method for plaque assay was developed. Infected DBT cells yielded high-titered virus and were a satisfactory source of complement-fixing viral antigen. The predominant cytopathic effect of MHV-2 in DBT cells was cell rounding and detachment, but no syncytial formation was observed. Fluorescent antibody staining revealed specific fluorescence only in the cytoplasm of infected DBT cells. In one-step growth experiment, newly formed virus was first recognized within 4-hr postinfection and showed subsequently a rapid exponential increase. Release of newly formed virus from the cell was rapid, and a continuous release lasted for a certain period of time. The average per-cell yield of active virus was estimated to be about 6–7 × 10² plaque-forming units.     

Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity

Within the last 3 years, genome-wide association studies (GWAS) have had unprecedented success in identifying loci that are involved in common diseases. For example, more than 35 susceptibility loci have been identified for type 2 diabetes and 32 for obesity thus far. However, the causal gene and variant at a specific linkage disequilibrium block is often unclear. Using a combination of different mouse alleles, we can greatly facilitate the understanding of which candidate gene at a particular disease locus is associated with the disease in humans, and also provide functional analysis of variants through an allelic series, including analysis of hypomorph and hypermorph point mutations, and knockout and overexpression alleles. The phenotyping of these alleles for specific traits of interest, in combination with the functional analysis of the genetic variants, may reveal the molecular and cellular mechanism of action of these disease variants, and ultimately lead to the identification of novel therapeutic strategies for common human diseases. In this Commentary, we discuss the progress of GWAS in identifying common disease loci for metabolic disease, and the use of the mouse as a model to confirm candidate genes and provide mechanistic insights.     

Mouse models expressing human carcinoembryonic antigen (CEA) as a transgene: evaluation of CEA-based cancer vaccines

In recent years, investigators have carried out several studies designed to evaluate whether human tumor-associated antigens might be exploited as targets for active specific immunotherapy, specifically human cancer vaccines. Not too long ago such an approach would have been met with considerable skepticism because the immune system was believed to be a rigid discriminator between self and non-self which, in turn, protected the host from a variety of pathogens. That viewpoint has been challenged in recent years by a series of studies indicating that antigenic determinants of self have not induced absolute host immune tolerance. Moreover, under specific conditions that evoke danger signals, peptides from self-antigen can be processed by the antigen-presenting cellular machinery, loaded onto the major histocompatibility antigen groove to serve as targets for immune intervention. Those findings provide the rationale to investigate a wide range of tumor-associated antigens, including differentiation antigens, oncogenes, and tumor suppressor genes as possible immune-based targets. One of those tumor-associated antigens is the carcinoembryonic antigen (CEA). Described almost 40 years ago, CEA is a M(r) 180-200,000 oncofetal antigen that is one of the more widely studied human tumor-associated antigens. This review will provide: (i) a brief overview of the CEA gene family, (ii) a summary of early preclinical findings on overcoming immune tolerance to CEA, and (iii) the rationale to develop mouse models which spontaneously develop gastrointestinal tumors and express the CEA transgene. Those models have been used extensively in the study of overcoming host immune tolerance to CEA, a self, tumor-associated antigen, and the experimental findings have served as the rationale for the design of early clinical trials to evaluate CEA-based cancer vaccines.     

Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers

Human N-Myc downstream-regulated gene 2 (NDRG2), located at chromosome 14q11.2, has been reported to be down-regulated and associated with the progression and prognosis of diverse cancers. Collectively, previous studies suggest that NDRG2 functions as a candidate tumor-suppressor gene; thus, up-regulation of NDRG2 protein might act as a promising therapeutic strategy for malignant tumors. The aim of this review was to comprehensively present the clinical and pathological significance of NDRG2 in human cancers.     

Mouse models of atherosclerosis

Atherosclerosis bears many features of a chronic inflammation that affects the intima of large and medium-sized arteries. In recent years apolipoprotein E-deficient and LDL receptor-deficient mice have been used to examine the effects of various gene products on the development of atherosclerosis. In the present review the effects of genetics, apolipoprotein E, inflammatory gene modifiers, lipoprotein modifications, lipoprotein receptors, vessel wall expression of lipoprotein-metabolizing enzymes, and the atheroprotective role of HDL on atherosclerosis in these mice are discussed. The importance of examining lesions that are more advanced than fatty streaks and careful histologic and immunologic examination of lesion composition is emphasized.     

Mouse models of laminopathies

The A‐ and B‐type lamins are nuclear intermediate filament proteins in eukaryotic cells with a broad range of functions, including the organization of nuclear architecture and interaction with proteins in many cellular functions. Over 180 disease‐causing mutations, termed ‘laminopathies,’ have been mapped throughout LMNA, the gene for A‐type lamins in humans. Laminopathies can range from muscular dystrophies, cardiomyopathy, to Hutchinson–Gilford progeria syndrome. A number of mouse lines carrying some of the same mutations as those resulting in human diseases have been established. These LMNA‐related mouse models have provided valuable insights into the functions of lamin A biogenesis and the roles of individual A‐type lamins during tissue development. This review groups these LMNA‐related mouse models into three categories: null mutants, point mutants, and progeroid mutants. We compare their phenotypes and discuss their potential implications in laminopathies and aging.     

Mouse models of human diseases: what can we learn?

Heightened interest in disease models is one very clear outcome of the Human Genome Project. Teams are now racing to identify the genes that cause disease, enabling the study of their function in mouse models for subsequent research into prevention and therapy. The simultaneous evolution of gene knockout and mutation technology in mice has provided the prime opportunity to facilitate the elucidation of genetic etiology of inherited disorders in humans. In this online supplement, leading scientists review such work by disease type, from Alzheimer's disease to DiGeorge syndrome. This valuable collection provides readers with timely, comprehensive reviews of mouse knockout and mutation research, including focus on single candidate gene knockouts to complex transgenics. We hope that you will find this supplement enjoyable and informative reading.     

Mouse models and type 2 diabetes: translational opportunities

Type 2 diabetes prevalence is increasing worldwide. Treatments are available, but glycaemic control is not always effective in many patients. Better models are needed to create new and improved therapies and to expand our understanding of how type 2 diabetes begins and progresses. Translational research involves the transformation of knowledge from basic scientific discoveries to impacting on public health. This can allow identification of novel molecular mechanisms underlying the disease which can lead to preventative measures, biomarkers for diagnosis, or future therapies. Generation of genetically modified mice has allowed us to investigate the function of genes and develop reproducible models in which the phenotype of the animal can be tested. Mouse models have already given us insight into glucose metabolism and insulin secretion, identified novel pathways, and have been used to confirm genome-wide association studies. In this review we discuss the use of the mouse to clarify human genome-wide association study loci, understand genes and pathways involved in type 2 diabetes, and uncover novel targets for drug discovery.