Abstract
Understanding how cancer cells migrate, and how this migration is affected by the mechanical and chemical composition of the extracellular matrix (ECM) is critical to investigate and possibly interfere with the metastatic process, which is responsible for most cancer-related deaths. In this article we review the state of the art about the use of hydrogel-based three-dimensional (3D) scaffolds as artificial platforms to model the mechanobiology of cancer cell migration. We start by briefly reviewing the concept and composition of the extracellular matrix (ECM) and the materials commonly used to recreate the cancerous ECM. Then we summarize the most relevant knowledge about the mechanobiology of cancer cell migration that has been obtained using 3D hydrogel scaffolds, and relate those discoveries to what has been observed in the clinical management of solid tumors. Finally, we review some recent methodological developments, specifically the use of novel bioprinting techniques and microfluidics to create realistic hydrogel-based models of the cancer ECM, and some of their applications in the context of the study of cancer cell migration.
Highlights
Cell migration is crucial for several physiological processes as diverse as tissue morphogenesis, immune cell trafficking, wound repair, and metastasis, one of the hallmarks of cancer malignancy [1,2]
We have shown representative examples that use hyaluronic acid (HA), collagen, and collagen mixed with Matrigel-based hydrogels at different concentrations to illustrate how microfluidics and hydrogels can be efficiently combined to perform relevant biological assays
Studying cell migration in vivo involves the use of animal models and intravital microscopy, which provides very relevant biological information but minimal experimental flexibility
Summary
Cell migration is crucial for several physiological processes as diverse as tissue morphogenesis, immune cell trafficking, wound repair, and metastasis, one of the hallmarks of cancer malignancy [1,2]. The range of confinement is altered by local remodeling of the ECM through various cell-mediated procedures including, lysyl oxidase family (LOX)-dependent ECM cross-linking, aberrant fiber deposition, or physical rearrangement of the matrix that clumps and align the fibrillar components These processes modify the mechanical properties of the ECM, especially the stiffness of the matrix, which causes MET reprogramming and tumor progression. Consistent with these observations, tumor malignancy is commonly associated with stromal rigidity and densification, and it has been described that Rho/ROCK signaling enhances tumor spread by promoting the alignment of stress fibers and actomyosin-dependent cell contractility through Arp2/3 and MLC proteins (Figure 3) [95] Both high-stiffness and highdensity substrates trigger specialized types of directed cell migration named durotaxis and haptotaxis. The dysregulation of one of these variables fatally alters cell behavior, triggering cellular malignancy and enhancing the ECM remodeling strategies and tumor dissemination
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