The effects of oxygen radical--mediated pulmonary endothelial damage on cancer metastasis.
The vascular bed of the lung is susceptible to environmental and host-mediated injury from free radicals. The lung is also a frequent site for the formation of cancer metastases. Since the circulation is important for the spread of cancer and because the endothelium is a barrier between the circulation and extravascular tissue, we have postulated that free radical damage to the pulmonary microvasculature enhances the formation of metastases. Pulmonary endothelial injury was induced in mice by bleomycin (120 mg/kg i.v.) or by exposure to 90% oxygen for 2-4 days. In rats, damage was elicited by intravenous injection of cobra venom factor which activates the circulating leukocytes. Endothelial damage was demonstrated by morphology and by measurement, in lung lavage fluids, of increased protein and/or leakage of 125I-albumin, previously injected intravenously. When radiolabeled cancer cells were injected into the tail vein during periods of pulmonary endothelial damage, there was a 3-36 fold increase in the numbers of these cells located in the lung after 24 hours. Subsequently more metastatic tumors formed in the animals with injured lungs. In rats, the enhanced localization was prevented by pretreatment of the animals with catalase or with antineutrophil antibodies. We have also demonstrated that stimulation of rat cancer cells by the chemotactic peptide N-fMLP is followed by chemiluminescence, amplified in the presence of luminol. Evidence for the generation of oxygen radicals by these cells includes inhibition of the response in the absence of oxygen or in the presence of superoxide dismutase, catalase, and mannitol, and dose-dependent reduction of acetylated cytochrome C. We conclude that free radical-mediated damage to the pulmonary endothelium significantly increases the metastasis of circulating tumor cells and we postulate that some cancer cells may directly facilitate their spread by generating free radicals.
Orr
F W
FW
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Adamson
I Y
IY
Warner
D
D
Leroyer
V
V
Werner
L
L
Shaughnessy
S
S
Young
L
L
D000818:Animals; D002196:Capillaries / Q000648:ultrastructure; D004546:Elapid Venoms / Q000633:toxicity; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D005609:Free Radicals; D008163:Luminescent Measurements; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008854:Microscopy, Electron; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009362:Neoplasm Metastasis; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D004546:Elapid Venoms; D005609:Free Radicals; C016310:cobra venom factor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010100:Oxygen