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The Role of Mouse Models

Early detection of cancer relies on the identification of particular markers of disease, including specific molecules or abnormal changes in genes or proteins. Changes in the levels of such biomarkers can often be measured at the very earliest stages of disease, even before the disease displays physical manifestations. Once biomarkers have been identified, researchers can develop assays and clinical tests that accurately measure their levels, thus giving clinicians the tools for disease management and treatment.

While the study of proteins provides researchers with numerous opportunities to glean highly specific insight into cancer processes at the molecular level, the breadth of possibilities generated by the complete spectrum of proteins (the proteome) is a limiting factor for analysis. Barriers to accurate analysis of serum proteins include:

• Proteins in serum can vary in concentration over a range of greater than 10 billion-fold. Unlike DNA, proteins cannot be amplified, making it difficult to pick up often critical trace amounts of material.
• It is possible that the abundant serum proteins (such as albumin) may act as carriers of less abundant proteins. Therefore, many important cancer biomarkers may be missed unless they can be separated from carriers prior to analysis.
• Separation of proteins and peptides from complex media such as serum is technically demanding and time consuming.
• Identification of post-translational modifications (addition of phosphate, sugars and other molecules to the proteins) and splice variants (similar proteins constructed from different lengths of the same RNA) requires specialized analytical techniques and sophisticated database searching.
• Variation in sample preparation and other experimental protocols between laboratories can significantly affect results.

Mouse Models

Mouse models of human cancer offer many distinct opportunities to optimize procedures for profiling major human cancers. The mouse serves as an in vivo model for cancer development that resembles the human model more closely than do cell lines and tissue samples. Mouse cells pass through many of the same physiological processes as human cells (such as apoptosis, angiogenesis, metastasis) during tumorogenesis. Researchers have previously elucidated many molecular pathways and frameworks of disease processes in mice, providing a framework that allows investigators to control many variables that could affect protein expression. By using the mouse model, researchers also gain the advantage of directly comparing aberrant protein levels measured in the mouse's cancer and surrounding tissues with those in the serum or plasma.

Mouse models of cancer also allow researchers to control many aspects of sample preparation and analysis that are difficult to control with human tissue samples. Because humans are genetically and environmentally diverse, each tumor site displays numerous clinical subtypes. Thus, it is highly unlikely that any set of human tissue samples will yield a set of biomarkers that is 100% specific for a given cancer tumor type. Moreover, human samples are currently processed at various clinical and research centers using a variety of protocols. However, inbred mice strains contain pre-engineered cancer-inducing genetic mutations, allowing laboratories to minimize heterogeneity, both in sample constitution and preparation.

As a result of these factors, mouse models provide a rapid testing ground for developing standards and protocols that can be translated to human clinical proteomics.