title: Calcium depletion reduces the destruction of fibrosarcoma cells in the microvasculature of artificially perfused rat hearts.
abstract: Earlier studies have shown that most tumour cells (TCs) injected into the circulation die rapidly. The mechanisms behind this rapid elimination of TCs are not known, but some experimental data suggest that mechanical trauma to the cells in the capillary bed plays a role. In the present investigation 725,000 rat fibrosarcoma cells (250,000/ml) were infused into the coronary microcirculation of isolated and artificially perfused (flow rate approx. 6 ml/min), beating and non-beating (Ca2+ excluded from the perfusate) rat hearts. The analyses included calculations of the number of TCs retained in the myocardium 5 min after start of TC infusion and their distribution within the ventricular wall. In addition, ultrastructural studies were performed to identify possible structural changes of trapped TCs and myocardial tissue. Intact and viable TCs in the effluent perfusate were counted. In beating hearts about 20% of the infused TCs were collected microscopically intact after passage through the heart circulation, and of these cells only 32% were viable (in-flow viability 87-91%). In Ca(2+)-depleted hearts the corresponding figures were 29 and 48%, respectively. The difference in viable cell counts was statistically significant (P less than 0.001). The TCs trapped in the left ventricular wall of the myocardium of beating hearts were mainly found in the subepicardial third of the wall, whereas in non-beating hearts the trapped cells were distributed randomly. The ultrastructural appearance of trapped cells differed between the two groups: 82% of cells trapped in beating hearts showed signs of severe damage, with subcellular vacuolization and plasmalemmal disruption, whereas 65% of cells trapped in Ca(2+)-depleted hearts seemed undamaged with intact cell membranes and cytoplasmic organization. The remaining 35% showed variable subcellular disorganization. The results cannot entirely be explained by mechanical TC damage in the microcirculation due to intracapillary deformation. The observations require additional explanatory mechanisms. One possible important TC damaging mechanism, dependent on extracellular Ca2+ levels, could be endothelial cell release of reactive oxygen species.
authors.affiliation: Department of Anatomy, University of Göteborg, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Nannmark
authors.forename: B R
authors.initials: BR
authors.lastname: Johansson
authors.forename: U
authors.initials: U
authors.lastname: Bagge
mesh_terms: D000818:Animals; D002118:Calcium / Q000172:deficiency / Q000494:pharmacology*; D002196:Capillaries / Q000473:pathology / Q000648:ultrastructure; D016923:Cell Death; D003326:Coronary Circulation; D004730:Endothelium, Vascular / Q000473:pathology / Q000648:ultrastructure; D005354:Fibrosarcoma / Q000139:chemically induced / Q000473:pathology* / Q000648:ultrastructure; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008748:Methylcholanthrene; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology*; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D008748:Methylcholanthrene; D002118:Calcium