A HUMAN FIBROSARCOMA INHIBITS SYSTEMIC ANGIOGENESIS AND THE GROWTH OFEXPERIMENTAL METASTASES VIA THROMBOSPONDIN-1

Concomitant tumor resistance refers to the ability of some large prima ry tumors to hold smaller tumors in check, preventing their progressiv e growth. Here, we demonstrate this phenomenon with a human tumor grow ing in a nude mouse and show that it is caused by secretion by the tum or of the inhibitor of angiogenesis, thrombospondin-1. When growing su bcutaneously, the human fibrosarcoma line HT1080 induced concomitant t umor resistance, preventing the growth of experimental B16/F10 melanom a metastases in the lung. Resistance was due to the production by the tumor cells themselves of high levels of thrombospondin-1, which was p resent at inhibitory levels in the plasma of tumor-bearing animals who become unable to mount an angiogenic response in their corneas. Anima ls carrying tumors formed by antisense-derived subclones of HT1080 tha t secreted low or no thrombospondin had weak or no ability to control the growth of lung metastases. Although purified human platelet thromb ospondin-1 had no effect on the growth of melanoma cells in vitro, whe n injected into mice it was able to halt the growth of their experimen tal metastases, providing clear evidence of the efficacy of thrombospo ndin-1 as an anti-tumor agent.