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An in Vivo Study of the Role of the Tumor Cell Cytoskeleton in Tumor Cell-Platelet-Endothelial Cell Interactions¹

Departments of Biological Sciences [J. D. T.], Radiation Oncology [H. C., K. K. N., J. D. T., K. V. H.], and Pathology [C. A. D., S. E. G. F.], Wayne State University, Detroit, Michigan 48202; Gershenson Radiation Oncology Center [J. D. T., K. V. H.], Detroit, Michigan 48201; and Laboratory Service, VA Medical Center [J. S. H., S. E. G. F.], Allen Park, Michigan 48101

We recently reported that disruption of tumor cell microfilaments or intermediate filaments resulted in an inhibition of the ability of tumor cells to induce the aggregation of homologous platelets in vitro (H. Chopra et al., Cancer Res., 48: 3787–3800, 1988). Previous investigators demonstrated that disruption of the tumor cell cytoskeleton decreases the ability of these cells to form lung colonies. We proposed that this latter effect is due, in part, to decreased interaction of tumor cells with platelets, following their arrest in the microvasculature. To test this hypothesis, B16 amelanotic melanoma cell microtubules, microfilaments, or vimentin intermediate filaments were disrupted with colchicine (50 µm), cytochalasin D (50 µm), or cycloheximide (50 µm), respectively, and then cells were tail vein injected into syngeneic mice. Both cytochalasin D- and cycloheximide-treated cells formed fewer lung colonies than did control cells. Colchicine, however, failed to inhibit lung colony formation. Neither colchicine nor cycloheximide treatment altered initial pulmonary arrest; however, fewer cycloheximide-treated cells remained in the lungs 8 h postinjection. Greater than 90% of control or colchicine-treated cells were found to be associated with activated platelets, and they also demonstrated typical cell membrane process formation 10 min and 8 h post-tumor cell injection. In contrast, less than 10% of cycloheximide-treated cells were in contact with activated platelets 10 min post-injection. However, by 8 h 90% of cycloheximide-treated cells were in contact with activated platelets. This recovery coincided with the reformation of the B16 amelanotic melanoma vimentin intermediate filament network and the reacquisition of the ability to induce platelet aggregation in vitro. Neither colchicine nor cycloheximide treatment altered initial B16 amelanotic melanoma cell adhesion to murine microvessel-derived endothelial cells. This study provides in vivo evidence in support of our previous findings that disruption of certain cytoskeletal elements (i.e., vimentin intermediate filaments) inhibits the tumor cell ability to activate platelets. This study also suggests that platelet activation may stabilize the initial tumor cell arrest in the microvasculature.

¹ This study was supported by NIH Grant CA 47115-02, a grant from Harper Grace Hospitals, and a grant from the Veterans Administration.

² To whom requests for reprints should be addressed.

Received 5/17/90. Accepted 8/30/90.

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