Effects of systemic complement activation and neutrophil-mediated pulmonary injury on the retention and metastasis of circulating cancer cells in mouse lungs.
Vascular pathways are major transit routes for the dissemination of malignant neoplasms and are also regulators of cancer metastasis, in part because the endothelium and vascular basement membrane are barriers to the entry and exit of tumor cells. In this study, we have examined the hypothesis that host cell-mediated damage to the pulmonary microvasculature facilitates the experimental metastasis of a syngeneic fibrosarcoma in the C57BL/6J mouse. Intravenous injection of purified cobra venom factor was followed in 30 minutes by complement activation, neutropenia with sequestration of neutrophils in the lung, and increased pulmonary vasopermeability. When syngeneic fibrosarcoma cells were injected simultaneously with cobra venom factor, there was a 3 fold increase in cancer cell retention in the lungs after 24 hours and a 3- to 20-fold increase in metastatic tumor burden after 14 days. Enhanced cancer cell retention after cobra venom factor was not seen in mice deficient in complement component C5 and was diminished by pretreatment of animals with antineutrophil antibodies, catalase, inhibitors of lipoxygenase, thromboxane synthetase, and lipid peroxidation (oxygen radical scavenger). We conclude that neutrophil-mediated microvascular injury can promote the organ localization and metastasis of circulating cancer cells.
Orr
F W
FW
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Warner
D J
DJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D003167:Complement Activation; D003182:Complement C5 / Q000502:physiology; D004546:Elapid Venoms / Q000037:antagonists & inhibitors / Q000506:poisoning; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology*; D009504:Neutrophils / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D003182:Complement C5; D004546:Elapid Venoms; D002374:Catalase