Despite many recent advances, cancer remains a leading cause of death in the United States. While many patients have benefited from the development of new approaches for diagnosis and treatment; ultimately, the most successful strategy for eradicating cancer will entail discovery of more effective means for its prevention, early detection, and early intervention. While genetically-engineered mouse (GEM) models of human cancer can greatly augment prevention research, to date, these models have not been widely exploited for prevention research. Here we consider the progress, potential, and pitfalls of using GEM models for prevention research, concluding with a discussion of how we can best capitalize on these models in the future. For a more in depth discussion of GEM models in cancer prevention the reader is referred to (1
GEM models of human cancer refer to mouse strains in which the genome has been manipulated to achieve gain- or loss- of oncogene or tumor suppressor gene function, respectively, the consequences of which are manifested in tumor phenotypes (2
). Similar to chemically-induced rodent models, which historically have been widely used in prevention research, GEM models provide an opportunity to investigate carcinogenesis in the context of the whole organism. However, GEM models are distinct from chemically-induced rodent models, since their tumor phenotypes are induced by manipulating a specific gene or genetic pathway rather than induction with carcinogens and/or other cancer promoting agents. Thus, GEM models enable the assessment of specific molecular pathways for tumorigenesis in the context of the whole organism.
GEM models are also distinct from xenograft models, which are typically based on the propagation of human tumors and/or cell lines in immune-deficient mice. While xenograft models have the obvious advantage of being developed from human cancer cells, they are often derived from established tumors or cancer cell lines (and very often from advanced tumors or metastases), and therefore are unlikely to precisely model early events in carcinogenesis. Moreover, since xenografts are propagated in immunodeficient mice, they do not recapitulate the contributions of the tumor microenvironment, bacterial flora, or host immune system for carcinogenesis, which is of considerable concern as it is becoming increasingly apparent that these play critical roles in carcinogenesis, particularly at early disease stages (3
However, critics of GEM models argue that their relevance for human cancer has not been established (6
), and cite examples in which studies in mouse models have not been validated to human cancer (see below). On the other hand, proponents of GEM models contend that the problem is not that the models aren’t relevant, but that the experimental parameters have not been designed in such as way as to effectively translate studies from mice to human cancer (7
). Indeed, the applicability of prevention studies done in GEM models of human cancer will invariably be dependent on the choice
of the model, the design
of the experiment, and many other logistical issues. Ultimately, for studies in GEM models to be applicable to humans, the models need to be appropriately chosen such that their biological and pathological properties are relevant for the experimental question being asked and, conversely, the experimental design of the study should be analogous to design of prevention research in humans.
Accordingly, it is imperative to establish criteria for evaluating the relevance of a particular GEM model for a given experimental paradigm. Such criteria should include: (1) Pathological analyses — does the model display histological and pathological features in common with human cancer or a sub-type thereof? (2) Disease evolution — does the model recapitulate the stages of disease progression as occurs in humans? (3) Tumor microenvironment — does the model effectively recapitulate the contribution of host factors including the tumor stroma, bacterial flora, and immune response for cancer progression? (4) Molecular pathways — does the model display relevant genetic, genomic, epigenetic, and/or proteomic alterations that are known to be relevant for their human counterpart? (5) Environmental factors — do hormonal, dietary, or other factors affect disease progression in the mouse models in a similar way as they do in humans?
Notably, it is often the case that in the course of characterizing these criteria for GEM models, new insights emerge that are relevant for understanding the molecular and biological properties of the human disease. Thus, analyses of GEM mice have elucidated critical biological mechanisms of tumorigenesis that provide new insights into human cancer, including as the critical role of telomere length in disease pathogenesis (10
) and more recently the role of cellular senescence in tumor suppression in vivo
). Similarly, comparative analyses of the molecular properties of mouse and human tumors have enabled the comprehensive analyses of global alterations in genomic pathways (12
), as well as the identification of specific genes that are novel biomarkers of disease outcome in humans (13
In the discussion that follows, we first provide a historical perspective on the types of GEM models that are available for prevention research (). Following which, we discuss past experiences using mouse models in prevention research and consider how these past experiences can impact the design of future studies. Finally, we consider opportunities for using GEM models as well as obstacles that need to be overcome to effectively capitalize on their application for prevention research.