Cancer Cell Heterogeneity in Resistance to Mechanical Trauma in the Microcirculation as Part of Metastasis

Abstract

Mechanical trauma in the microcirculation contributes to the inefficiency of the metastatic process in terms of cancer cells, even though the process progresses and ultimately kills many patients. A filtration model was developed to assess qualitatively the kinetics of the damage and survival of cancer cells in passing through narrow channels, demonstrating that under physiologic capillary pressures, deformability is a traumatic event which kills the majority of cells passing through. Immediate damage to more than 90 percent of cells from the initial input was internal, reflected in impaired reproductive integrity (³H-TdR incorporation) and metabolism (¹⁴C-AA incorporation). Analogous loss of plasma membrane integrity and ultimately cell death were not apparent until 96h after filtration. A “dormant” state was observed in the approximately 10 percent surviving fraction until 214h (L1210 cells) and 240h (EAT cells). Regular doubling time was resumed thereafter. The amount of damage and lower survival rates correlated inversely with the input cell concentration and shear rate and directly with pore size. Recovery from the trauma of deformamation was dependent on the spatial association of the cell and nuclear diameters and the components of the cytoskeleton and cell periphery. This portion of the work thus introduces an interesting concept that mechanical trauma induced in passing through narrow vessels under physiologic conditions can have a significant effect on the kinetics of circulating cancer cells. The second part of this study was designed to determine whether survival from trauma is random or whether it is a manifestation of a trauma-resistant subpopulatlon. However, “wild” (heterogenous) as well as clonal subpopulations derived from filtration-trauma survivors were destroyed and recovered at the same rate as the original “wild” parental population. Thus, the work supports the concept that survival from mechanical trauma is a random event and that resistance is not hereditary.