Thrombospondin-1-mediated metastasis suppression by the primary tumor human melanoma xenografts

Some cancer patients show accelerated growth of pre-existing metastases aft er removal of the primary tumor. The purpose of this study was to investiga te 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 b earing D-12, U-25, or thrombospondin-1 overexpressing R-18 tumors, which sh owed high thrombospondin-1 expression and secreted large quantities of thro mbospondin-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 growt h of their own spontaneous metastases. The anti-angiogenic and antimetastat ic effects of D-12 and U-25 tumors were blocked in mice treated with thromb ospondin-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 macro-colonies 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-angio genic therapy involving thrombospondin-1.