PART I. BASIC RESEARCH Introduction to Basic Research

Since Stephen Paget’s “seed-and-soil” theory was published in 1889, a wealth of research has focused on the cascade of events involved in the spread of cancer cells from the primary tumor to secondary organs. As Paget highlighted, in addition to the intrinsic properties of metastatic cancer cells, features of the microenvironment in target organs of metastasis are also critical for successful tumor dissemination. Over the past century, metastasis research has focused predominantly on the genetic and phenotypic properties that confer the “seed” with a migratory and invasive phenotype. More recently, the contributions of cells, the extracellular matrix, and secreted factors in the metastatic microenvironment have gathered attention. In addition, although it was traditionally thought thatmetastasis occurred as a late event during tumor growth, there are now several lines of evidence to suggest that the onset of metastatic progression occurs early during carcinogenesis. The contributors to this book have made seminal contributions toward furthering our understanding of the molecular and cellular pathways in tumor dissemination. As outlined here, their chapters highlight the key scientific advances as well as the modern models and tools for studying metastasis. The first four chapters focus on the state-of-the-art models and systems employed in metastasis research. In Chapter 1, Janet E. Price describes animal models of metastasis. Such in vivo approaches have distinct advantages over in vitro assays, allowing real-time study of the multistep processes of metastasis in its physiological context. Even so, there are limitations to the application of animal models, such as the relatively low number of tumor cell lines that are available. In addition, animal models often use immunodeficient hosts, thereby eliminating important immune cell and stromal cell contributions to themetastatic process. The development of improved models of metastasis using both cell lines and genetically engineeredmodels is required. In Chapter 2, Elisa C. Woodhouse and Kathleen Kelly discuss the advantages of studying metastasis with genetic models in Drosophila and zebrafish. The advantages of thesemodels are to rapidly generate mutations in vivo and specifically examine their effects on the metastatic process. In Chapter 3, Wayne S. Kendal provides an alternative approach to studying metastasis, describing how mathematical models executed by computer may be used to simulate complex biological systems. This approach enables predictions of system behavior, testing of hypotheses, the understanding of complex data, and the development of newhypotheses. In Chapter 4, CristinaHidalgoCarcedo and Eric Sahai describe the use of intravital imaging, the high-resolution optical sectioning of live tissue that provides unique, real-time insights into events occurring within tumors. Genetic studies remain the predominant focus of cancer research; comparing the genetic characteristics of metastatic tumor cells with those of primary tumor cells remains a relatively new field of study. Devanand Sarkar and Paul B. Fisher explore these studies in Chapter 5. The targeting of specific genetic pathways identified by these studies may prevent seminal steps in the metastatic process, including extravasation, survival in the bloodstream, intravasation, and/or growth at a new organ site. In Chapter 6, Brunilde Gril and colleagues discussmetastasis suppressor genes, which prevent spontaneous metastasis without affecting primary tumor growth. A common trait of highly metastatic tumors is their ability to adapt the topology of local and distant microenvironments to better aid their progression. In Chapter 7, Bedrich L. Eckhardt and coworkers review the role of the stroma during metastatic progression and highlight that the propensity to metastasize to certain organs requires homing mechanisms that involve specific ligand/receptor interactions. They discuss the use of phage-display technology to discover novel endothelial markers that may be used to disrupt tumor progression and metastasis. In Chapter 8, Amaia