Compressive Stress Inhibits Proliferation in Tumor Spheroids through a Volume Limitation

Abstract

In most instances, the growth of solid tumors occurs in constrained environments and requires a competition for space. A mechanical crosstalk can arise from this competition. In this article, we dissect the biomechanical sequence caused by a controlled compressive stress on multicellular spheroids (MCSs) used as a tumor model system. On timescales of minutes, we show that a compressive stress causes a reduction of the MCS volume, linked to a reduction of the cell volume in the core of the MCS. On timescales of hours, we observe a reversible induction of the proliferation inhibitor, p27Kip1, from the center to the periphery of the spheroid. On timescales of days, we observe that cells are blocked in the cell cycle at the late G1 checkpoint, the restriction point. We show that the effect of pressure on the proliferation can be antagonized by silencing p27Kip1. Finally, we quantify a clear correlation between the pressure-induced volume change and the growth rate of the spheroid. The compression-induced proliferation arrest that we studied is conserved for five cell lines, and is completely reversible. It demonstrates a generic crosstalk between mechanical stresses and the key players of cell cycle regulation. Our results suggest a role of volume change in the sensitivity to pressure, and that p27Kip1 is strongly influenced by this change.

Self-Driven Jamming in Growing Microbial Populations

“…This finding is consistent with the view of the late G1 checkpoint as an integrator of numerous stresses, including osmotic, chemical and heat shock stresses [36][37][38]. Force-induced cell cycle arrest has been observed in mammalian cells [39,40], but the associated mechanical stresses are two to three orders lower than the stalling pressure measured in our experiments.…”

Tumor proliferation and diffusion on percolation clusters

“…Both the simulation and the clinical results were consistent with each other. These results were also confirmed and proved by previous studies that showed that the inhomogeneous environment could influence tumor proliferation and invasion through compressive stress [42][43][44]70]. The most common metastasis site for breast cancer is bone (48%), followed by lung (26%), liver (30%) and brain (7%) [6][7][8].…”

“…Therefore, we speculated that a percolation cluster with a different occupation probability should be suitable for describing the proliferation and spread of a tumor in an inhomogeneous surrounding matrix, which itself should be compressive to tumor proliferation and invasion. The results are basically in accordance with previous studies that showed that the surrounding matrix possesses a specific external pressure on a solid tumor [42][43][44]70]. …”

“…Huang et al found that endothelial cells exert mechanical stress on a tumor; endothelial cells were seeded on reduced adherent surfaces to increase their cytoskeletal tension [40]. Delarue et al found that the surrounding matrix behaves as a compressive stress and causes a reduction of the volume of multicellular tumor spheroids (MTS), leading to a reduction of the cell volume in the core of MTS; the surrounding tissue can be viewed as a restraint environment for tumor progression [41,42]. Cheng et al [43], Desmaison et al [44], and Deisboeck et al [45] also observed that the surrounding extracellular matrix (ECM) possesses a specific external pressure as well as tumors' interstitial pressure on a solid tumor, affecting considerably the migration of tumor cells.…”

Simulating tissue mechanics with agent-based models: concepts, perspectives and some novel results

“…The same mechanism could explain different growth speeds in expanding one-cell thick dense monolayers observed by Bru et al [90], and growth saturation of multicellular spheroids in agarose gel [62,82,144] observed by Helmlinger et al [11], and Galle et al [153]. Recently Delarue et al [154] confirmed inhibition of proliferation in tumor spheroids by compressive stress.…”