Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells.
BACKGROUND
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.


RESULTS
We 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
Our 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.
Cheng
Gang
G
Edwin L. Steele Laboratory of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Tse
Janet
J
Jain
Rakesh K
RK
Munn
Lance L
LL
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D048430:Cell Shape; D017931:DNA Primers; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D012685:Sepharose; D013314:Stress, Mechanical; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D012685:Sepharose