Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment.

More than 90% of cancer-related deaths can be attributed to the occurrence of metastatic diseases. Recent studies have highlighted the importance of the multicellular, biochemical and biophysical stimuli from the tumor microenvironment during carcinogenesis, treatment failure, and metastasis. Therefore, there is a need for experimental platforms that are able to recapitulate the complex pathophysiological features of the metastatic microenvironment. Recent advancements in biomaterials, microfluidics, and tissue engineering have led to the development of living multicellular microculture systems, which are maintained in controllable microenvironments and function with organ level complexity. The applications of these "on-chip" technologies for detection, separation, characterization and three dimensional (3D) propagation of cancer cells have been extensively reviewed in previous works. In this contribution, we focus on integrative microengineered platforms that allow the study of multiple aspects of the metastatic microenvironment, including the physicochemical cues from the tumor associated stroma, the heterocellular interactions that drive trans-endothelial migration and angiogenesis, the environmental stresses that metastatic cancer cells encounter during migration, and the physicochemical gradients that direct cell motility and invasion. We discuss the application of these systems as in vitro assays to elucidate fundamental mechanisms of cancer metastasis, as well as their use as human relevant platforms for drug screening in biomimetic microenvironments. We then conclude with our commentaries on current progress and future perspectives of microengineered systems for fundamental and translational cancer research.