Biology & Physiology Research
The biology and physiology research questions for which researchers employ mice often relate to confirming that the observations made in cell or multi-cell culture settings hold up when these same properties of cancer are studied in an intact animal system. Oftentimes observations from cells differ from animal results because features of the local micro-environment, or architecture of a tissue, immune system responses, or systemic effects change the functioning of individual cells. Although cell culture will continue to provide crucial insights, it is clear that larger systems-level studies will be required to understand the complexity of many disease situations. Crucial components of the research on biology and physiology of cancer models include optimizing and standardizing fixation and testing protocols. Making these standard operating procedures, and the resulting data, available to researchers using appropriate computational archival resources is also necessary.
Many routes of exploration involving mouse models have yielded important information about basic biology and physiology, and also cancer-related biology and physiology. Inbred mice with specific characteristics such as increased incidence of mammary cancer helped to identify the role of mouse mammary tumor virus (MMTV). This provided insight not only to the role of an oncogenic virus, but also to cellular pathways that are triggered during tumor development. Strain background has also provided insights into progression and metastasis, including features in breast cancer, lung cancer, brain cancer, and skin cancer models, and aspects of biology such as vascularization which may be important in tumor formation for many different types of cancer. The roles that the immune system may play in the onset of cancer are being elucidated with a variety of mouse model systems. The exploration of more basic mechanisms of DNA repair that enable carcinogenesis are also performed in mouse model systems, and may offer utility for understanding and intervening in many types of cancer.
Mice with various types of targeted mutations in genes that have been implicated in cancer have led to deep understanding of the roles of these genes and the pathways in which they participate. For example, BRCA1 is a well-studied gene in both humans and mice, and extensive understanding of its normal biological functions in DNA repair, and its role in breast cancer, has been gleaned from mouse models. In some cases several genes with impact can be combined and the results examined in mice. Another example of a well-characterized single gene situation that is informative is the case of the role of the APC gene in colon cancer. Further details have emerged that indicate the role of APC may also vary by tissue, which can teach us more about the effects of differential gene expression in tissues. The monogenic investigations, and the subsequent pathway details, offer deep insights into the biology of cancer initiating cells and tissues in both normal and abnormal conditions, and offer routes for therapeutic interventions.
However, it is also apparent that many of the occurrences of cancer incidence outside of the laboratory will not be tied to a single gene, but more of a summation of many smaller impacts of a number of different genes or epigenetic changes and environmental influences. These multi-factorial influences and networks are challenging to study, but need to be assessed to enable us to understand the complex nature of cancer. As more genomes (and more human cancer genomes), and more genome-wide association studies (GWAS) become available, researchers will turn to the mouse to elucidate many of the potentially important variations they encounter. Cross-species genomic analyses will become powerful strategies to gain knowledge of the important players in cancer biology.
A variety of coordinated projects have been initiated to perform large-scale assessments and phenotyping of mouse models. These will likely yield insights into spontaneous cancer occurrences. They will also provide foundations to compare inbred mice and those with targeted mutations in cancer biology investigations. Systematic phenotyping (also known as phenogenomics) with standard protocols will provide a wealth of data that will be available to researchers, and provide functional annotation to provide insights into genomic features. These results can be employed in the important arena of comparative pathology that will provide crucial answers about the differences between normal and pathological aspects of cancer.
Not only will these projects identify important cancer-related genes, they will help researchers to select appropriate strains and models for other types of tests they may want to perform.