Abstract
Growing solid tumors are subjected to mechanical stress that influences their growth rate and development. However, little is known about its effects on tumor cell biology. To explore this issue, we investigated the impact of mechanical confinement on cell proliferation in MultiCellular Tumor Spheroids (MCTS), a 3D culture model that recapitulates the microenvironment, proliferative gradient, and cell-cell interactions of a tumor. Dedicated polydimethylsiloxane (PDMS) microdevices were designed to spatially restrict MCTS growth. In this confined environment, spheroids are likely to experience mechanical stress as indicated by their modified cell morphology and density and by their relaxation upon removal from the microdevice. We show that the proliferation gradient within mechanically confined spheroids is different in comparison to MCTS grown in suspension. Furthermore, we demonstrate that a population of cells within the body of mechanically confined MCTS is arrested at mitosis. Cell morphology analysis reveals that this mitotic arrest is not caused by impaired cell rounding, but rather that confinement negatively affects bipolar spindle assembly. All together these results suggest that mechanical stress induced by progressive confinement of growing spheroids could impair mitotic progression. This study paves the way to future research to better understand the tumor cell response to mechanical cues similar to those encountered during in vivo tumor development.
Highlights
A tumor micro-region consists of a heterogeneous cancer cell population organized in a 3D structure in which cell growth is influenced by interactions with the microenvironment
In addition to growth-induced solid or stored stress, which are generated by cell and matrix tumor components, reciprocal forces from the surrounding environment opposed to tumor growth can contribute to the stress experienced by a tumor cell population
We investigated the impact of a confined mechanical environment on cell proliferation in micro-tumors and our findings suggest that growth-associated external mechanical stress impairs mitosis progression
Summary
A tumor micro-region consists of a heterogeneous cancer cell population organized in a 3D structure in which cell growth is influenced by interactions with the microenvironment. The crosstalk between tumor cells and microenvironmental components, including the extracellular matrix (ECM), fibroblasts, endothelial and immune cells, is essential for tumor progression and drug resistance [1,2]. In such complex environment, tumor growth and progression is influenced by biochemical parameters such as growth factors, cytokines, hormones or hypoxia, and by mechanical cues [3,4]. Cells sense forces through mechanoreceptors that are located at the plasma membrane and that transduce the information to the intracellular machinery to elicit a specific response to external mechanical cues [6]. Modification of the mechanical environment can modulate tumor cell growth [7], migration and invasion [7,8,9,10] as well as proliferation and apoptosis [11,12]
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