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 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.     

Specific cytosol binding proteins for 25(OH)D3 and 1.25(OH)2D3 in human breast cancers

Binding proteins for 1.25 (OH) 2D3 were investigated in thirty breast cancers. Human breast cancer was shown to contain specific, high affinity cytosol binding proteins for 1.25 (OH) 2D3 and 25 (OH) D3. The binding protein for 1.25 (OH) 2D3 sedimented at 3.7 S and the binding protein for 25 (OH) D3 at about 6.0 S on sucrose density gradient analysis containing 0.3 M KCl and 1 mM dithiothreitol in buffer. Kd for 1.25 (OH) 2D3 were from 0.1 x 10(-11) M to 7.1 x 10(-11) M measured by Scatchard plots. Competition binding studies indicated that the relative specificity of the binding protein for 1.25 (OH) 2D3 much greater than 25 (OH) D3 greater than 1 alpha (OH) D3, 24,25 (OH)2D3 greater than D3 much greater than Estradiol-17 beta. 1.25 (OH) 2D3 receptor-positive was detected in twenty-eight out of thirty breast cancers.     

Brain Gene Expression of a Sporadic (icv-STZ Mouse) and a Familial Mouse Model (3xTg-AD Mouse) of Alzheimer’s Disease

Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and may result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations of presenilins or amyloid-β (Aβ) precursor protein (APP). A commonly used mouse model for AD is 3xTg-AD mouse, which is generated by over-expression of mutated presenilin 1, APP and tau in the brain and thus represents a mouse model of FAD. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse, shows many aspects of SAD. Despite the wide use of these two models for AD research, differences in gene expression between them are not known. Here, we compared the expression of 84 AD-related genes in the hippocampus and the cerebral cortex between icv-STZ mice and 3xTg-AD mice using a custom-designed qPCR array. These genes are involved in APP processing, tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related protein kinases, glucose metabolism, insulin signaling, and mTOR pathway. We found altered expression of around 20 genes in both mouse models, which affected each of above categories. Many of these gene alterations were consistent with what was observed in AD brain previously. The expression of most of these altered genes was decreased or tended to be decreased in the hippocampus of both mouse models. Significant diversity in gene expression was found in the cerebral cortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the 3xTg-AD mice, whereas more genes related to insulin signaling and glucose metabolism were down-regulated in the icv-STZ mice. The present study provides important fundamental knowledge of these two AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.     

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 of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

The prevalence of non-alcoholic fatty liver disease (NAFLD) increases year by year, and as a consequence, NAFLD has become one of the most prevalent liver diseases worldwide. Unfortunately, no pharmacotherapies for NAFLD have been approved by the United States Food and Drug Administration despite promising pre-clinical benefits; this situation highlights the urgent need to explore new therapeutic targets for NAFLD and for the discovery of effective therapeutic drugs. The mouse is one of the most commonly used models to study human disease and develop novel pharmacotherapies due to its small size, low-cost and ease in genetic engineering. Different mouse models are used to simulate various stages of NAFLD induced by dietary and/or genetic intervention. In this review, we summarize the newly described patho-mechanisms of NAFLD and review the preclinical mouse models of NAFLD (based on the method of induction) and appraises the use of these models in anti-NAFLD drug discovery. This article will provide a useful resource for researchers to select the appropriate model for research based on the research question being addressed.     

Mouse models with human immunity and their application in biomedical research

Biomedical research in human beings is largely restricted to in vitro studies that lack complexity of a living organism. To overcome this limitation, humanized mouse models are developed based on immunodeficient characteristics of severe combined immunodeficiency (SCID) or recombination activating gene (Rag)^null mice, which can accept xenografts. Peripheral constitution of human immunity in SCID or Rag^null mice has been achieved by transplantation of mature human immune cells, foetal human thymus, bone marrow, liver tissues, lymph nodes or a combination of these, although efficiency needs to be improved. These mouse models with constituted human immunity (defined as humanized mice in the present text) have been widely used to investigate the basic principles of human immunobiology as well as complex pathomechanisms and potential therapies of human diseases. Here, elements of an ideal humanized mouse model are highlighted including genetic and non-genetic modification of recipient mice, transplantation strategies and proposals to improve engraftments. The applications of the humanized mice to study the development and response of human immune cells, human autoimmune diseases, virus infections, transplantation biology and tumour biology are reviewed as well.