The hemodynamic destruction of intravascular cancer cells in relation to myocardial metastasis.

Abstract

A variety of observations in humans and experimental animals indicate that large numbers of circulating cancer cells are killed in the microvasculature. It is suggested that this occurs when friction or adhesion between individual cancer cells and capillary walls results in an increase of tension in the cancer cell peripheries above a critical level because of (blood) pressure differentials between their free ends. Hemodynamic and anatomic data relating to the myocardial circulation and deformability measurements on four types of rat cancer cells have been reported previously by others. Novel calculations based on these data suggest that the increased tension at the peripheries of cancer cells passing through the myocardial capillaries will exceed the critical levels for rupture. Analysis of autopsy data for solid tumors reveals a low (<3%) incidence of myocardial metastases in the absence of lung metastases and a higher (15%) incidence in their presence. One explanation for these observations is that, in the absence of lung metastases, relatively few of the cancer cells enter the coronary arteries from primary tumors with systemic venous drainage because many are retained or destroyed in transit through the pulmonary vasculature, and most of those delivered to the myocardium then suffer hemodynamic destruction. In the presence of pulmonary metastases, large numbers of viable cancer cells are liberated directly into the pulmonary venules and subsequently are delivered to the myocardium without prior exposure to the arterial side of the microcirculation. The combined effects of increased delivery and the protective effects of arrested cells on those preceding them in ifies along the capillaries account for the higher incidence of myocardial metastases. It is proposed that hemodynamic destruction of circulating cancer cells may be an important underlying cause of metastatic inefficiency, together with other cytocidal mechanisms.Metastasis and patterns of metastasis are major considerations in the diagnosis and treatment of patients with cancer. In this communication, certain aspects of the development of metastatic patterns will be discussed against the background of mechanical damage inflicted on cancer cells in their transit through the microvasculature.Cancer cells delivered to organs in their arterial blood fall into three groups: (i) some pass through the vasculature and emerge in the venous blood in the viable state; (ii) other cancer cells are arrested in the microvasculature, and of these comparatively few survive to give rise to metastases; and (iii) many are gradually released with loss of reproductive integrity. The proportions of circulating cancer cells falling into each of the three groups varies with the type of cancer cell and involved organ. For example, in the rat, 98% of AH100B hepatoma cells were killed by one transit of the pulmonary vasculature, compared with only 8% of AH66F hepatoma cells (1). Other quantitative studies revealed that most W256 cancer cells injected into the tail-vei...

Paucity of Muscle Metastasis in Otherwise Widely Disseminated Cancer

“…18 In contrast, blood-borne cancer cells have been demonstrated to have a greater survivability in denervated, noncontracting muscle than in physiologically normal functioning muscle. 19 Muscle www.ajpmr.com Paucity of Muscle Metastasis in Cancer contraction, in addition to contributing to an increase in tumorigenicity, may also generate sufficient turbulence to dislodge tumor emboli, which might otherwise implant in this tissue. Tumor cells escape from the microcirculation by multiple routes, either by migrating through the endothelial cell layer of the vessel wall by invading intercellular junctions or more directly by entering the endothelial cell itself by penetrating pseudopodia and by intravascular multiplication of sufficient size to rupture the host vessel.…”

Calcium depletion reduces the destruction of fibrosarcoma cells in the microvasculature of artificially perfused rat hearts

“…This should be related to the estimated myocardial capillary diameter (5.0-5.1/~m; see also Potter and Groom [18]), which was near but still above the critical diameter where membrane damaging deformations would occur. Furthermore, it appears that although TCs have been observed in the vital microscope to die while being extremely deformed in narrow muscle capillaries [7], a large percentage of TCs infused into muscle quickly pass across the capillary bed [9]. This rapid passage probably takes place through the wide capillaries of each arteriole-capillary-venular network, as has been described for leukocytes [19], and should not impose membrane damaging deformations.…”

“…In fact, there is some evidence from experimental studies on the liver [2,3], lungs [4], myocardium [5] and skeletal muscle [6] that most TCs die within 2-3 min in the microcirculation. The mechanisms behind this very rapid killing of the TCs have not been clarified but several experimental studies have indicated that mechanical trauma may be at least partly responsible [5][6][7][8]. This theory is based on the assumption that the considerable deformations undergone by the TCs when entering the microvascular bed may cause lethal damage to the cell by membrane rupture.…”

Biomechanical interactions of cancer cells with the microvasculature during hematogenous metastasis

“…Cancer cells trapped in capillary beds in muscle are expected to be subject to addition mechanical trauma during muscle contraction; a suggestion supported by the relatively low incidence of metastasis in the myocardium and striated muscle in early metastatic disease [26], and by in vivo experiments. In mice, it was shown [37] that following left ventricular injections (LVI), some 5% of injected cancer cells became arrested in the myocardium.…”

“…Reduction in film thickness below a critical amount, will then permit interactive forces to occur between the two surfaces creating friction which, if in excess of the driving force due to blood-pressure, will result in cancer cell arrest. Attempts were made to assess the feasibility of this hypothesis, using well-accepted formulations from the field of fluid dynamics [26,24]. Essentially, comparisons were made between cancer cell transit times through capillary segments, with the times taken to produce the necessary filmthinning, for the generation of interaction (arresting) forces.…”