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Promotion of Pulmonary Metastasis in Mice by Bleomycin-induced Endothelial Injury¹

From the Department of Pathology, University of Manitoba, Winnipeg, Manitoba, R3E 0W3, Canada

The passage of circulating tumor cells across the vascular wall is an important step in the evolution of cancer metastases. Since tumor cells attach preferentially to subendothelial matrix at sites of endothelial injury and retraction in vitro, we have used an established in vivo model of pulmonary endothelial damage to examine the effects of endothelial injury on the localization and metastasis of circulating tumor cells in vivo. C57BL/6 mice were given a single i.v. dose of bleomycin (120 mg/kg) or multiple i.p. injections (10 mg/kg, twice weekly for 6 wk). Five days after the single injection or 4 days after the last i.p. injection, 2 x 10⁵ [¹³¹I] iododeoxyuridine-labeled fibrosarcoma cells or unlabeled cells were injected i.v. Two to 8 times as many labeled cells were found in the lungs of bleomycin-treated animals after 24 h. Two and 3 wk after injecting unlabeled fibrosarcoma cells, 1.4 to 5 times more metastatic lung colonies were counted in bleomycin-treated animals than in controls. Morphometric analysis of histological sections demonstrated that the percentage of lung area occupied by tumor in bleomycin-treated animals was between 4 and 16 times that of controls. Analysis of bronchoalveolar lavage fluids demonstrated 5-fold increases of total protein content and leakage of previously injected ¹²⁵I-labeled albumin, indicating increased endothelial permeability. Electron microscopic examination of lungs of bleomycin-treated mice demonstrated endothelial retraction with exposure of the underlying basement membrane. Electron microscopy of [³H]thymidine-labeled tumor cells, located by autoradiography, demonstrated their attachment to exposed basal lamina. Data from these experiments in vivo support the hypothesis that endothelial damage can facilitate the metastasis of circulating tumor cells.

¹ This work was supported by a grant from the Council for Tobacco Research USA, Inc. (F. W. O., I. Y. R.) and a grant from the National Cancer Institute of Canada (F. W. O.).

² Present address: Department of Pathology and Oncology Research Group, McMaster University Medical Center, 1200 Main Street West, Hamilton, Ontario, Canada, L8N 3Z5. To whom requests for reprints shall be addressed.

Received 4/15/85. Revised 9/30/85. Accepted 10/ 2/85.

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