The sequence of events in haematogenous metastasis from colonic carcinoma was analysed, using 1541 necropsy reports from 16 centres. The findings are consistent with the cascade hypothesis that metastases develop in discrete steps, first in the liver, next in the lungs and finally, in other sites. Deviations of necropsy findings from the cascade model are largely explained on the basis of false negative reports. In only 216 of 1194 cases was there suggestive evidence that metastatic patterns (excluding lymph nodes) were causally related to lymphatic or non-haematogenous pathways. The incidence of metastatic involvement in 'other' (quaternary) sites correlated with target organ blood-flow (ml min-) per g, only when bone marrow and thyroid were excluded. In the thyroid the incidence was lower than expected on the basis of blood flow per g tissue; this may indicate that the thyroid is an unfavourable site for metastatic growth of colonic carcinoma. In the bone marrow it is higher; the latter may be due to delivery of cancer cells via both arterial blood and the vertebral venous plexus. Recognition of this pattern of metastases in the bone marrow could be important with respect of diagnosis and therapy, in patients with colonic carcinoma.

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An attempt is made to clarify some general concepts of hematogenous metastatic patterns in humans, by the use of autopsy data. The significance and problems associated with 'false negative' reports are assessed. By the use of metastatic efficiency indices in which the incidence of specific target organ involvement is related to organ blood-flow, 'seed-and-soil' effects are discriminated from the effects of differential cancer cell delivery. An analysis of autopsy data from cases with a history of colorectal carcinoma is used to illustrate the importance of metastasis from metastases in the genesis of hematogenous metastatic patterns in humans.

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.

Metastasis is a major, life-threatening complication of cancer. The bloodstream is the most important disseminative route for cancer cells liberated from their parent tumors. Single circulating cancer cells are arrested in the microvasculature, where the vast majority are killed by rapid or slow processes, and the relatively few survivors grow into micrometastases. We review the underlying causes of one type of rapid cancer cell death in the microcirculation, namely, that caused by biomechanical interactions of cancer cells with microvessel walls, which may result in cell surface membrane expansion and lethal rupture. These lethal interactions appear to be important rate-regulators in hematogenous metastasis, and to dictate some aspects of metastatic patterns. Although these are not the only interactions involving cancer cells, in contrast to others involving cellular and humoral defense mechanisms, they have received comparatively little attention.