Engineering approaches for investigating tumor angiogenesis: exploiting the role of the extracellular matrix

Abstract

A major paradigm shift in cancer research is the emergence of multidisciplinary approaches to investigate complex cell behaviors, to elucidate regulatory mechanisms and to identify therapeutic targets. Recently, efforts are focused on the engineering of complex in vitro models, which more accurately recapitulate the growth and progression of cancer. These strategies have proven vital for investigating and targeting the events that control tumor angiogenesis. In this review, we explore how the emerging engineering approaches are being used to unlock the complex mechanisms regulating tumor angiogenesis. Emphasis is placed on models using natural and synthetic biomaterials to generate scaffolds mimicking the extracellular matrix, which is known to play a critical role in angiogenesis. While the models presented in this review are revolutionary, improvements are still necessary and concepts for advancing and perfecting engineering approaches for modeling tumor angiogenesis are proposed. Overall, the marriage between disparate scientific fields is expected to yield significant improvements in our understanding and treatment of cancer.

Figure 1. Overview of engineering-based approaches utilized for investigating angiogenesis

Upper panel: 3D ECM scaffolds are utilized to investigate tumor-EC interactions (A) in vitro and (B) in-vivo. Middle panel: Micropatterning is utilized (A) to evaluate vascular cell behaviors on geometrically patterned arrays of ECM, (B) to investigate tumor cell behaviors on ECM proteins to evaluate (i) angiogenic cytokine secretion and (ii) adhesion and migration, and (C) to assess tumor-EC interactions including (i) tumor cell-directed invasion of ECs into gels and (ii) ECs and tumor cells co-culture in 3D ECM scaffolds. Lower panel: Microfluidic devices are utilized (A) to evaluate vascular cell responses to physical and chemical gradients, delineate the tumor-EC interactions taking place within a controlled environment and (B) to study vascular morphogenesis taking place in the presence and absence of tumor cells in 3D ECM scaffolds. Drawing not to scale.