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.
Rofstad
E K
EK
Group of Radiation Biology and Tumor Physiology, Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway. e.k.rofstad@labmed.uio.no
Graff
B A
BA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008545:Melanoma / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012878:Skin Neoplasms / Q000098:blood supply / Q000473:pathology*; D019700:Thrombospondin 1 / Q000276:immunology / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019700:Thrombospondin 1