Chapter 13 Models of Metastasis in Drug Discovery James E. Talmadge By definition, animal models provide only an approximation of clinical reality. One reason for this, for example, is that although metastases are the primary cause of mortality fi'om neoplasia, by are rarely considered a target in drug discovery and development. Due to the impact of metastasis on clinical disease, we posit that metastasis should be considered in drug discovery, in addition, to more tradi- tional biologic concepts, including drug pharmacology and toxicity. Drug discovery and developmental studies can incorporate orthotopic and spontaneolls metastasis models (syngeneic and xenogeneic) with their inherent host-tumor microenvironmental interactions, in addition to confirmatory autochthonous and/or genetically engineered models (GEMs). This requires a rational and hierarchical approach using models of metastatic disease optimally using resected, orthotopic primary tumors and clinically relevant outcome parameters. In this chapter, we provide protocols for models of metastasis that can be used in translational and drug discovery studies. Key words: Metastasis, autochthonous tumors, genetically engineered tumor models, orthotopic tumors, spontaneous metastasis. 1. Introduction Mouse models are critical for the discovery and development of novel therapeutics; however, research has been minimally success- ful in decreasing the age-adjusted death rate for cancer. In 2003, for the first time since 1930, when epidemiological records were initiated, fewer people «85 years old) died of cardiac disease as compared to cancer (1). This historic change was due to a 60%, 70%, and 0% decrease in mortality by heart disease, stroke and cancer, respectively. Tumor initiation, progression and metasta- sis, in contrast, represent a complex, multifactorial process that G. Proetzel, MV. Wiles (eds.), Mouse Models for Drug Discovery, Methods in Molecular Biology 602, 10.1007/978-1-60761-058-8_13, © Humana Press, a part of Springer Science+Business Media, LLC 2010 215