Antiangiogenic treatment with thrombospondin-1 enhances primary tumor radiation response and prevents growth of dormant pulmonary micrometastases after curative radiation therapy in human melanoma xenografts.
Thrombospondin-1 (TSP-1) is a potent antiangiogenic factor that has been shown to inhibit tumor growth by preventing endothelial cells from responding to a wide variety of angiogenic stimulators. We have demonstrated previously that D-12 primary tumors (human melanoma xenografts) suppress the growth of their spontaneous pulmonary micrometastases by secreting TSP-1 into the blood circulation. The same tumor model was used in the present work to study antitumor effects of combined radiation therapy and antiangiogenic treatment with TSP-1. Curative radiation treatment of D-12 primary tumors resulted in rapid growth of previously dormant micrometastases. Growth of dormant micrometastases could be prevented by treating the host mice with exogenous TSP-1 after the radiation treatment. Treatment with exogenous TSP-1 after subcurative radiation treatment reduced the growth rate of recurrent primary tumors in addition to suppressing metastatic growth. TSP-1 suppressed tumor growth at both primary and metastatic sites by inducing apoptosis in tumor-associated microvascular endothelial cells. Treatment with exogenous TSP-1 before radiation treatment enhanced the antitumor effect of the radiation treatment. The radiopotentiation by TSP-1 involved at least two distinctly different mechanisms, i.e., TSP-1 reduced the fraction of radiobiologically hypoxic parenchymal tumor cells and increased the radiation sensitivity of the tumor microvasculature by promoting radiation-induced endothelial cell apoptosis. In conclusion, the present preclinical study showed that TSP-1 has antiangiogenic, antimetastatic, and radiopotentiating properties that merit additional investigation in clinical studies.
Rofstad
Einar K
EK
Group of Radiation Biology and Tumor Physiology, Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. e.k.rofstad@labmed.uio.no
Henriksen
Kristin
K
Galappathi
Kanthi
K
Mathiesen
Berit
B
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy* / Q000556:secondary; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019700:Thrombospondin 1 / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D019700:Thrombospondin 1