Matrix Modulus Affects Invasion Rate of Tumor Cells through Synthetic Hydrogels
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Matrix Modulus Affects Invasion Rate of Tumor Cells through Synthetic Hydrogels Esmaiel Jabbari Biomimetic Materials and Tissue Engineering Laboratory, University of South Carolina Columbia, SC 29208, U.S.A. ABSTRACT Understanding factors affecting cell invasion influences the design of engineered constructs for tissue regeneration. The objective of this work was to investigate the effect of matrix stiffness on invasion of tumor cells through a synthetic hydrogel with well-defined properties. A novel star acrylate-functionalized polyethylene glycol-co-lactide (SPELA) macromer was synthesized to produce hydrogels with well-defined water content, elastic modulus, degree of crosslinking and hydrophilicity. The hydrogel was formed by photopolymerization of the macromer with or without integrin-binding cell adhesive RGD peptide. Cell invasion experiments were carried out in a transwell with SPELA hydrogel as the invading matrix and 4T1 mouse breast cancer cells. The invading cells on the lower membrane side were counted with an inverted fluorescent microscope. The concentration of SPELA macromer ranged from 10-25 wt% and that of RGD ranged from 1x10-4 to 1x10-2 M. The shear modulus of the hydrogel varied from 200 Pa to 25 kPa as the SPELA concentration increased from 10 to 25 wt%. Cell invasion slightly increased with increasing RGD concentration. However, RGD concentration >1% resulted in a significant decrease in cell migration. As the matrix stiffness increased from 0.15 to 0.4, 3, 5, 6, 14, and 25 kPa the invasion rate decreased from 18.0 to 5.5, 6, 5.7, 5.2, 1.5, and 1.0 cells/mm2/h, respectively. There was a sharp decrease in invasion rate for matrix stiffness greater than 10 kPa. Results demonstrate that matrix stiffness plays a major role in invasion of tumor cell through a gelatinous matrix.
INTRODUCTION Cell migration and invasion are central to many biological events like embryonic development, tissue morphogenesis, tumor metastasis, wound healing, and immune response [1,2]. Directed invasion of progenitor cells from the host tissue to the scaffold, due to the gradient in growth factors, are central to the success of the tissue-engineered (TE) implants. Understanding cell-matrix and intracellular forces responsible for invasion in synthetic matrices not only allows us to investigate the underlying mechanism of many pathological processes but also holds promise for designing improved engineered constructs for tissue regeneration. At the cellular scale, migration is manifested by cell locomotion consisting of (a) pseudopod protrusion at the leading edge, (b) formation of focal contacts between the cell surface receptors and the substrate to generate traction, (c) actomyosin contraction of the cytoskeleton for generation of contractile force, and (d) detachment of the trailing edge and relaxation of the cytoskeletal
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network to a new configuration. When cells move in 3D and invade a matrix, there is an additional step of focalized matrix degradation after the formation of local contacts [3]. It is well-esta
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