Abstract
BackgroundCompressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved.Methodology/Principal FindingsWe co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway.Conclusions/SignificanceOur results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation.
Highlights
The growth of solid tumors is strongly influenced by its microenvironment
Several key questions remain unanswered, including: (1) What is the nature of the stress field around growing tumor spheroids? (2) Can local solid stress distribution affect the shape of tumor spheroids? (3) Does solid stress distribution affect cell phenotype in different regions of individual spheroids? (4) What is the intracellular pathway that regulates the solid stress-induced phenotypic change(s)? These questions are critical for a fundamental understanding of solid tumor growth dynamics
We show that the accumulating solid stress in agarose gels around growing tumor spheroids can be measured using co-embedded fluorescent micro-beads as markers for strain in the gel: agarose gels are resistant to degradation by cancer cell proteinases [13], and allow studies of solid stress accumulation independent of cell invasion
Summary
The growth of solid tumors is strongly influenced by its microenvironment. Besides well-studied microenvironmental parameters, such as hypoxia [1,2] and angiogenesis [3,4,5], mechanical stresses play an important role. Various hypotheses have been proposed regarding the involvement of mechanical stresses in tumor development [8,9,10,11], and Helmlinger et al [12] conducted the first quantification of spheroid growth inhibition in agarose gels They found that human colon carcinoma spheroids can grow to a maximum size of 400 mm (diameter) in 0.5% (w/v) agarose, but only 50 mm in 1.0% agarose (which is less compliant). Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved
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