Modeling the Mechanobiology of Cancer Cell Migration Using 3D Biomimetic Hydrogels

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.

An Innovative Customized Biomimetic Hydrogel for Drug Screening Application Potential: Biocompatibility and Cell Invasion Ability

“…Historically, most synthetic polymers have lacked biological ligands, such as peptide, that can directly bind to cell surface receptors [13]. Therefore, Arg-Gly-Asp (RGD) peptide conjugated with polymer was reported to increase cell adhesion and proliferation [14][15][16][17]. In a previous study, PF127 and Gly-Arg-Gly-Asp (GRGD) peptide as a sequence RGD peptide were successfully prepared as 3BE hydrogel for in vitro cell culture application [9].…”

Biophysical interactions between components of the tumor microenvironment promote metastasis

“…Actin is the primary component of the cytoskeleton, a main mediator for intercellular force generation and a key component for cell spreading and adhesion. Reorganization of the actin cytoskeleton is important for the transition of epithelial-like cells to mesenchymal-like cells through a well-characterized process, known as epithelial–mesenchymal transition (EMT) in embryogenesis (Kalluri and Weinberg 2009 ; Thiery et al 2009 ; Morales et al 2021 ). This is a crucial step in detachment of tumor cells from the epithelium and the invasion of the ECM.…”

“…After the activation and increase of integrin adhesions, their maturation into focal adhesions has been noted (Butcher et al 2009 ; Harris et al 2018 ). The extracellular part of an integrin interacts with matrix proteins, including collagen and fibronectin, while the intracellular part recruits focal adhesion proteins, including mechanosensors (e.g., talin, vinculin), signaling molecules (e.g., focal adhesion kinase), helping to form the focal adhesion complex (FA) and actin binding proteins (e.g., filamin, a-actinin) (Morales et al 2021 ). All these contribute to the connection between integrins and the cytoskeleton (Wozniak et al 2004 ).…”

“…It has been proven that this protein has a critical role in cell motility and stiffness, as it provides contractile forces inside the cell. These forces are generated through intracellular tension, as a result of myosin II activity and contractility and are essential for the controlled detachment of the rear of a cell from the substratum and enhancement of actin polymerization at the leading front part of the cell (Deree et al 2006 ; Elkhatib et al 2014 ; Fukumoto et al 2015 ; Jalilian et al 2015 ; Morales et al 2021 ).…”

Microfluidics-Based Single-Cell Research for Intercellular Interaction

“…Matrigel is derived from the basement membrane (BM) of the Engelbreth-Holm-Swarm (EHS) mouse sarcoma; It is often crosslinked with collagen for intercellular intercation study. Additionally, there are many (semi)synthetic-based hydrogels [e.g., polyethylene glycol (PEG), polylactic acid (PLA), or poly(lactic-co-glycolic acid) (PLGA)] used for modeling the ECM (Morales et al, 2021). Unlike native biomaterials, they do not exhibit functional ligands for cells and hence require crosslinking with native proteins or chemical insertion of matrix metalloproteinase (MMP)-sensitive peptides and integrin-binding domains [RGD (Arg-Gly-Asp) motifs].…”