Collaborative Action of Surface Chemistry and Topography in the Regulation of Mesenchymal and Epithelial Markers and the Shape of Cancer Cells

Abstract

Malignant transformation is associated with enhancement of cell plasticity, which allows cancer cells to survive under different conditions by adapting to their microenvironment during growth and metastatic spread. Much effort has been devoted to understanding the molecular mechanisms of these processes. Although the importance of the extracellular matrix and of surface properties in these mechanisms is evident, the direct impact of distinct physical and chemical surfaces characteristics on cell fate remains unclear. Here, we have addressed this question using HT1080 fibrosarcoma cells as a model. To examine the relationship between surface topography, chemistry, and cell behavior, hydrophobic poly(butyl methacrylate-co-ethylene dimethacrylate) (BMA-EDMA) and hydrophilic poly(2-hydroxyethyl methacrylate-co-ethylene dimethacrylate) (HEMA-EDMA) surfaces with three different topographies (microporous, nanoporous, and nonporous) were generated. These surfaces were then modified by photoinitiated grafting of three different methacrylate monomers to create surface chemistry gradients of either negatively (AMPS) or positively (META) charged or zwitterionic (MDSA) functionalities. Our results show that AMPS promotes cell spreading, but that META abolishes cell growth. META and MDSA grafted on microporous BMA-EDMA produced superhydrophilic surfaces with high globularity and elasticity, which modified the cell phenotype by inhibiting cell spreading, followed by loss of mesenchymal characteristics and a reduction in protein levels of the mesenchymal markers N-cadherin, beta-catenin, p120 catenin, and also of the adaptor proteins vinculin and paxillin that are associated with adhesion and cancer cell invasion. The effect was strengthened along the gradient, suggesting that the density of the functional groups plays a role in this process. On the nanoporous surface, only MDSA grafting resulted in a significant increase in cell number, a reduction in N-cadherin expression, increased beta-catenin and p120 catenin levels, as well as the appearance of the epithelial marker E-cadherin. This indicates that the cancer cells have a high plasticity that is triggered by the collaborative effect of physical and chemical surface properties.

Differential and Interactive Effects of Substrate Topography and Chemistry on Human Mesenchymal Stem Cell Gene Expression

“…However, a different set of modifications on topography and surface chemistry was used in their study. Therefore, the level of synergistic effects may depend on different combinations of abiotic culture conditions [61]. …”

Multifunctional Biomaterials: Combining Material Modification Strategies for Engineering of Cell-Contacting Surfaces

“…continued such as neurons, 129,130 or on cellular transformation into cancer. 131 Thereby, shape-restriction of biochemical ligands could be used to guide and control cell attachment and differentiation on biomaterial surfaces. For example, MSC displayed more and larger focal adhesions as well as enhanced differentiation toward the osteogenic fate on 100 nm deep indentations, modified with RGD, compared to those with 10 nm depth.…”

“…One aim of combining surface topography with chemical functionalities was to understand and mimic (at least partially) the influence of the ECM on stem cell differentiation, ,, skeletal muscle tissue engineering, , peripheral nerve regeneration, and development of functional cells, such as neurons, , or on cellular transformation into cancer . Thereby, shape-restriction of biochemical ligands could be used to guide and control cell attachment and differentiation on biomaterial surfaces.…”

Nanoscale Topographies for Corneal Endothelial Regeneration

“…The addition of instructive topographies on cell culture scaffolds could, therefore, provide significant advantages compared to conventional flat (smooth) 2D substrates, as the first can offer biophysical cues that more closely replicate those present in the native ECM. Surface topographies have already been shown to modulate mesenchymal-to-endothelial/epithelial transition [23][24][25][26] and vice versa [27][28][29][30] in several others applications. However, research focusing on the interaction between hCECs and surface topography of the culture substrate remains relatively less explored compared to other (corneal) cell types, despite the fact that growing evidence (as reported in the next sections as well as from preliminary work by our group) is showing that subcellular topographies can also have a significant impact on hCECs' expansion and differentiation.…”