Thrombospondin-1 treatment prevents growth of dormant lung micrometastases after surgical resection and curative radiation therapy of the primary tumor in human melanoma xenografts

PURPOSE: Intradermal D-12 human melanoma xenografts develop pulmonary micrometastases in BALB/c nu/nu mice, and these metastases are kept dormant for prolonged times, because the primary tumor secretes thrombospondin-1 (TSP-1) into the blood circulation of the host. In this study, we report on the development of macroscopic metastases after surgical resection and curative radiation treatment of the primary tumor, the mechanisms involved, and the effects of treating the host with exogenous TSP-1 after the eradication of the primary tumor. METHODS AND MATERIALS: Xenografted tumors of the D-12 human melanoma were used as tumor model. Macroscopic metastases were scored by using a stereomicroscope. Micrometastases were detected by histologic examinations. Angiogenesis was studied by using an intradermal angiogenesis assay. Apoptotic endothelial cells were detected by immunohistochemistry by using an in situ apoptosis detection kit. RESULTS: Surgical resection as well as curative radiation treatment of the primary tumor resulted in accelerated growth of dormant micrometastases. This growth could be prevented by treating the host with exogenous TSP-1 after the surgery or the irradiation. Endogenous and exogenous TSP-1 prevented metastatic growth by suppressing angiogenesis, i.e., by inducing apoptosis in activated endothelial cells adjacent to dormant micrometastases. CONCLUSIONS: TSP-1 has antiangiogenic and antimetastatic effects that should be investigated further in clinical studies. Cancer patients with TSP-1-producing primary tumors may benefit from combined local treatment and antiangiogenic/antimetastatic treatment with TSP-1.