Quantification of metastatic tumor growth in bleomycin-injured lungs

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Abstract
The lung is a common target organ in experimental models of tumor metastasis in which quantification usually involves counting labeled tumor cells shortly after injection, or enumeration of grossly visible pleural tumors. In this study, these approaches were used in addition to autoradiographic and morphometric methods to analyse the effect of bleomycin-mediated injury on the development, distribution and quantification of pulmonary metastases. One day after intravenous injection of 2 × 105 fibrosarcoma cells, the lungs of C57 bl/6 mice, pretreated with bleomycin (120mg/kg i.v., 5 days before) contained about nine times as many [131 I] iododeoxyuridine-labeled cells as the lungs of control animals given saline injections. At this time, autoradiographic counts of [3H] thymidine-labeled tumor cells in lung sections showed a similar increase in tumor cell localization after bleomycin, with labeled cells distributed equally between parenchymal and pleural areas. However, subsequent tumor growth was demonstrated microscopically to be predominantly in pleural and peribronchial areas, especially at sites of lung injury induced by bleomycin. Counts of grossly visible pleural tumors failed to demonstrate a difference between bleomycin groups and controls at 7 days whereas counts of nodules in lung sections, and quantification of lung area occupied by tumor both showed significantly greater tumor involvement in bleomycin-treated animals. As tumors became confluent, morphometric measurements demonstrated tumor growth in the lung more accurately than did nodule counts. We conclude that bleomycin-induced injury greatly enhances metastatic tumor growth and that morphometric methods are more sensitive than lung colony counts in their ability to quantify pulmonary metastases. Morphometry and autoradiography have also demonstrated that while there is a uniform distribution of arrested tumor cells in the lung initially, there is preferential development of metastatic tumors at sites of pulmonary damage, in particular at the pleura.