Thrombospondin-1-Mediated Metastasis Suppression by the Primary Tumor in Human Melanoma Xenografts

Some cancer patients show accelerated growth of pre-existing metastases after removal of the primary tumor. The purpose of this study was to investigate whether primary tumor-induced metastasis suppression can be mediated by thrombospondin-1 in melanoma. Human melanoma xenografts (D-12, R-18, and U-25) were used as models of melanoma in humans. Melanoma angiogenesis, lung colonization, and spontaneous pulmonary metastasis were inhibited in mice bearing D-12, U-25, or thrombospondin-1 overexpressing R-18 tumors, which showed high thrombospondin-1 expression and secreted large quantities of thrombospondin-1 into the blood, but not in mice bearing wild-type R-18 tumors, which were negative for thrombospondin-1. D-12 tumors suppressed the growth of their own spontaneous metastases. The anti-angiogenic and anti-metastatic effects of D-12 and U-25 tumors were blocked in mice treated with thrombospondin-1 neutralizing antibody. Dormant avascular microcolonies having an elevated apoptotic activity were seen in the lungs of mice bearing D-12 or U-25 tumors, whereas only neovascularized lung macrocolonies were seen in control and antibody-treated mice. This study suggests that some melanoma patients may benefit from combined local treatment and long-term anti-angiogenic therapy involving thrombospondin-1.