Three dimensional in vitro tumor platforms for cancer discovery

Abstract

Traditional experimental platforms to study cancer biology consist of two-dimensional (2D) cell culture systems and animal models. Although 2D cell cultures have yielded fundamental insights into cancer biology, they do not provide a physiologically representative three-dimensional (3D) volume for cell attachment and infiltration. These systems also cannot recapitulate critical features of the tumor microenvironment including hemodynamics, matrix mechanics, cellular crosstalk, and matrix interactions in a dynamic manner, or impose chemical and mechanical gradients. While animal models provide physiologic fidelity, they can be highly variable and cost prohibitive for extensive biological investigation and therapeutic optimization. Furthermore, the interplay of many different microenvironmental variables, such as growth factors, immune reaction, and stromal interactions, make it difficult to isolate the effect of a specific stimulus on cell response using animal models. Due to these limitations, 3D in vitro tumor models have recently emerged as valuable tools for the study of cancer progression as these systems have the ability to overcome many of the limitations of static 2D monolayers and mammalian systems. Initial 3D in vitro models have consisted of static 3D co-culture platforms and have been successful in providing a deeper insight compared to animal and static 2D systems. However, the majority of these existing systems lack the presence of physiological flow, a pivotal stimuli in tumor growth and metastasis and important consideration for transport of diagnostic or therapeutic agents. In order to consider the influence of flow on cancer progression microfluidic platforms are being widely used. The integration of microfluidic technology and microfabrication techniques with tumor biology has resulted in complex 3D microfluidic platforms capable of investigating various key stages in cancer evolution including angiogenesis and metastasis. 3D microfluidic platforms are able to provide a physiologically representative tumor environment while allowing for dynamic monitoring and simultaneous control of multiple factors such as cellular and extracellular matrix composition, fluid velocity and wall shear stress, and both biochemical and mechanical gradients.