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Phenotyping Mice Cancer Models

In order to better understand both normal and abnormal situations in organisms or in various tissues, a number of techniques are used to assess the state, content, or responses to stimuli or treatments in mice. Phenotyping refers to the strategies used to understand the biological consequences of genomic variation, alteration, or outcomes that may or may not be related to DNA content or features in cells.  For example, stress on an animal could cause alterations in blood pressure or circulating hormones, elicit changes in gene expression in various tissues, affect food intake, and alter many more aspects of biology. These reactions can be measured and compared with control animals or other strains to find informative leads about underlying biological mechanisms.  Depending on the focus of the research, any number of protocols and tools can be used to assess the biological state. The techniques and directions will be highly dependent on the research topic, tissue, and conditions involved. Here we provide a framework for finding helpful phenotyping resources and strategies that may be useful. 

Phenotyping strategies will vary depending on the stage of the animal’s life under investigation as well.  When creating models, prenatal phenotypes can be a complicating issue. If prenatal phenotypes are lethal, there will be no animals to evaluate. If phenotypes are developmentally damaging, it may be challenging to determine when the defect initiates.  Postnatal phenotyping will employ different methods depending on the age and sex of the animals.  For additional details on assessing phenotypes of mutant mice, you may want to examine Mouse Phenotypes: A Handbook of Mutation Analysis. Additional guidance may be obtained by scrutinizing protocols from phenotyping projects. The Mouse Phenome Project aims to aid researchers with phenotyping strategies and data.  EUMORPHIA, a large-scale project in Europe has generated standardized protocols and data collection about mice.  A standardized phenotyping ontology has been developed to describe the observations, and enables cross-species comparisons. Many other strategies developed for individual projects will offer guidance on the approaches that may be useful for researchers depending on their focus.  The Mouse Phenome Database (MPD) has a collection of protocols that have been used for specific projects that may also provide helpful directions.  Searching MPD data specifically for cancer phenotypes provides access to data and literature that may offer utility.

Physical phenotyping and imaging

Traditional phenotyping of animals has relied on measurements of various features of the body, body functions, tissue structure and composition, and responses such as hearing, vision, or behavior.  Many tools and strategies for investigating physiology, metabolism, pathology, and behavior of mice are in wide use.  Tissue histology methods have long been used to examine the structure and organization of tissues in normal and pathological situations. In some cases tissue staining with dyes and chemicals visible with light microscopy are employed.  Increasingly, less invasive methods for visualizing cells, tissues, and whole body systems are becoming available for small animals.  Special dyes and imaging methods are advancing and refining the opportunities for these types of investigations.

Molecular phenotyping

Performing molecular phenotyping to assess the gene transcripts, protein biomarkers and protein modifications that may be observed in normal tissues, tumors, and treatment settings is also becoming increasingly refined.  Bioinformatics support for assessing the results continue to develop as well. Detection of changes in gene expression patterns at the mRNA or protein level can elucidate patterns of genes that are up-regulated or down-regulated and provide informative diagnostic signatures. PCR, array technologies and next-generation sequencing strategies may be used on RNA.  Various protein biomarkers are used as diagnostic indicators for cancerous changes, and can be detected via a range of mass-spectrometry technology, immunological detection methods, or using fluorescently-tagged proteins in mice.  Detection of protein modifications such as phosphorylation or dephosphorylation states can provide indications of biological activity that lead to clues about pathways involved in tumorigenesis. These types of investigations can be genome-wide, or can target specific pathways of interest.