The acquisition of a metastatic phenotype is the most deadly trait a tumor can develop. Secondary tumors compromise organ function, are refractory to standard chemotherapeutics, and ultimately lead to the demise of the patient. Although tumor progression contains stochastic elements, there is an emerging pattern of organotropism, as various cancers display a predilection to metastasize to distinct secondary sites. A common trait of highly metastatic tumors is the ability to adapt the topology of local and distant microenvironments to better aid their progression. Indeed, many metastasis-regulating genes are components of, or require interactions with, stromal cells or the extracellular matrix (ECM) to exert proper function [1–4]. As such, the propensity to metastasize to specific sites is controlled in part by endemic homing mechanisms that involve coordinated ligand–receptor interactions between the cancer cell and the host microenvironment. Despite large advances in our understanding of metastasis biology, the molecular mechanisms guiding these processes remain largely uncharacterized.

Combinatorial phage-display libraries are a powerful screening tool that can readily identify functional protein interactions in vivo. Their utility has revealed that the stromal microenvironment – specifically the vasculature – of an organ contains a unique “molecular address” that can be modulated during inflammation, tumor growth, and metastasis [3, 5–7]. This chapter explores the role of the stroma during metastatic progression and highlights how phage display technology has been used to discover novel endothelial markers that disrupt tumor progression and metastasis.