The tumor microenvironment is increasingly recognized as an important contributor to the processes of growth, invasion, and metastasis. Molecular and cellular targets within the microenvironment may thus offer new and fruitful targets for therapeutic intervention. However, progress in understanding and clinically leveraging this regulation has been limited by the complexity of the in vivo microenvironment, which does not easily allow clear dissection of specific regulatory effects. This in turn has created a strong need for in vitro engineered model systems that offer highly precise and independent control of a variety of extracellular parameters that can faithfully recapitulate the tumor microenvironment. In this chapter, we review recent progress in the development of such systems. We discuss microenvironmental signals that regulate tumor growth in vivo, focusing on the extracellular signals a cell receives in the most critical steps in
cancer progression, including tumor initiation, growth, and metastasis. We then review strategies that have been developed to recreate in vitro important aspects of the cancer microenvironment. Building upon and adapting the lessons learned from tissue engineering, we then prospectively explore two specific paradigms that may enable improved dissection of in vitro signals: decellularized matrices and synthetic matrices. 11.1 IntroductionCancer remains one of the deadliest diseases in the United States, claiming more than 577,000 lives in 2012 alone. American men and women face lifetime probabilities of developing cancer of 45% and 38%, respectively . Despite this high incidence and the pressing need for effective treatments, decades of intensive research have only produced a slow decline in mortality rates, suggesting an urgent need to revisit our traditional understanding of tumor progression and broaden the search for potential therapeutic targets.An important goal in modern cancer therapeutics, including surgical resection, chemotherapy, and radiation therapy, is to selectively destroy or impair tumor cells while minimizing collateral damage to normal host cells. While radiation and systemic chemotherapy are certainly cytotoxic, their imperfect selectivity produces devastating side effects that frequently limit their deployment in the clinic. As a result, there has been an emphasis on improved characterization of tumor heterogeneity to identify the most important tumor-populating cells as well as the development of increasingly cancer-specific therapeutic approaches based on selective targeting of tumor cells based on their aberrant metabolism, receptor expression, or signal transduction.