Lethal deformation of cancer cells in the microcirculation: A potential rate regulator of hematogenous metastasis

Abstract

The hypothesis has been advanced that deformation-induced lethal mechanical trauma, resulting in surface-membrane rupture, is inflicted on circulating cancer cells trapped in the microcirculation, and that this rapid cell-killing mechanism is a potentially important rate regulator for hematogenous metastasis. We describe and discuss an in vivo test of this hypothesis. Vital fluorescence microscopy was performed on the microcirculation of cremaster muscle preparations in mice, following retrograde injections into the femoral artery of acridine orange-stained sarcoma cells. Cancer cells having mean diameters of 16.5 microns in suspension, were deformed from spheres into cylinders having a mean length of 53 microns, in 7-microns diameter capillaries. Most of these cells were dead several minutes after injection. It was estimated that sphere-to-cylinder shape-transitions of this magnitude required an average increase of 52% in apparent cell surface area. Evidence is presented that most of this apparent increase was achieved by non-lethal surface "unfolding", utilizing membrane "excess". That cancer-cell deformation of the magnitude observed in vivo is the direct cause of lethal, surface-membrane rupture was indicated by the observed loss of membrane integrity in cells deformed from spherical to cylindrical shape in vitro, by aspiration into micropipettes of capillary dimensions. The experimental observations are therefore consistent with the hypothesis.

Arrest of B16 Melanoma Cells in the Mouse Pulmonary Microcirculation Induces Endothelial Nitric Oxide Synthase-Dependent Nitric Oxide Release that Is Cytotoxic to the Tumor Cells

“…32,33 Deformation-induced mechanical trauma and immune-mediated host cell killing have also been implicated in the intravascular death of tumor cells. 31,34,35 The data that we have presented here demonstrate that the local release of NO at the site of tumor cell arrest contributes to this intravascular cytotoxicity although the limited survival of tumor cells even in mice deficient in eNOS would suggest that other factors must play a role as well.…”

“…23,30,31 Wong and colleagues 32 demonstrated that this cell death in the lung was because of apoptosis and the observations of our lab in the liver would suggest that the death of these cells by apoptosis is a frequent event. 5 The importance of apoptosis in the regulation of pulmonary metastasis is evident both because inhibition of apoptosis by overexpression of bcl-2 leads to more metastasis and because metastatic cells undergo markedly less apoptosis than nonmetastatic cells after arrest in the lung.…”

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

“…Mechanical forces created by arrest can not only cause tumor cell deformation to kill the cells by surface-membrane rupture, 25 but can also trigger the release of NO in the sinusoids, which is cytotoxic to the tumor cells, and cause them to undergo apoptosis and/or necrosis. 9,10 Our previous studies have demonstrated that the rate of apoptosis is significantly higher in the sinusoids compared to the TPV.…”

Circulating tumour cells in breast cancer: Prognostic indicators, metastatic intermediates, or irrelevant bystanders? (Review)

“…An estimated 1x10 6 tumour cells are released into the bloodstream on a daily basis (32). The majority of these are destroyed by the immune system (33), while many more are destroyed by haemodynamic forces (34). A very small proportion of extravasated CTCs (~2%) are capable of dividing and forming micro-metastases, while an even smaller number (0.02%) can evolve into fullyfledged distant tumours (35).…”