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Rupture of Cancer Cells Under Microcirculatory Conditions

Survival of circulating tumor cells (CTCs) in blood circulation is essential for cancer metastasis. However, fluid forces in microcirculation have been shown to cause cell rupture, lending to the notion that such mechanical trauma of CTCs is responsible for metastatic inefficiency. Literature evidence for tumor cell death due to mechanical damage remains ambiguous and moreover the physical mechanisms of cell rupture are poorly understood. Here, we develop a microfluidic capillary model of microcirculation that contains an array of flow bifurcations and investigate rupture of tumor cells. We find that when a cancer cell arrives at a narrow bifurcation, it is temporarily arrested, followed by strong cellular deformation causing a cytosol‐filled membrane‐bound vesicle to be pinched‐off. The vesicle size was found to increase with the size of tumor cell suggesting that the cytosol content is larger for bigger cells. To identify the essential features of the mechanism underlying the rupture process, we used a library of drugs that (i) either enhance or inhibit the polymerization of actin and microtubules (ii) inhibit myosin II and decrease cortical tension, and (iii) condense and decondense nuclear chromatin. Results from these studies show that the cytoskeletal elements and membrane play an important role in regulating the time‐scale for rupture of tumor cells, but not the nucleus. The vesicle size was not sensitive to any of the drug treatments indicating again that the cytosol content determines the vesicle volume. Collectively, the drug studies support the poroelastic model of a cell, where under mechanical stress, the cytosol flows through the elastic cytoskeleton and fills the membrane that is detached from the cortex. Experiments with different cancer cell lines showed that highly metastatic cells take longer to rupture suggesting that their cytoskeleton and membrane properties are different than weakly metastatic cell lines. Finally, we find that less than 5% of the fragmented tumor cells undergo apoptosis, suggesting that CTCs can survive the impact of fluid forces in microcirculation and that mechanical trauma is not a significant cause for metastatic inefficiency.