Concomitant tumor resistance refers to the ability of some large primary tumors to hold smaller tumors in check, preventing their progressive growth. Here, we demonstrate this phenomenon with a human tumor growing in a nude mouse and show that it is caused by secretion by the tumor of the inhibitor of angiogenesis, thrombospondin-1. When growing subcutaneously, the human fibrosarcoma line HT1080 induced concomitant tumor resistance, preventing the growth of experimental B16͞F10 melanoma metastases in the lung. Resistance was due to the production by the tumor cells themselves of high levels of thrombospondin-1, which was present at inhibitory levels in the plasma of tumor-bearing animals who become unable to mount an angiogenic response in their corneas. Animals carrying tumors formed by antisense-derived subclones of HT1080 that secreted low or no thrombospondin had weak or no ability to control the growth of lung metastases. Although purified human platelet thrombospondin-1 had no effect on the growth of melanoma cells in vitro, when injected into mice it was able to halt the growth of their experimental metastases, providing clear evidence of the efficacy of thrombospondin-1 as an anti-tumor agent.Concomitant tumor resistance is an unusual phenomenon wherein animals harboring large primary tumors are resistant to the growth of distant smaller tumors (reviewed in refs. 1 and 2). This resistance depends on circulating factors and disappears upon surgical resection of the primary tumor. In stunning advances over the past several years, O'Reilly and Folkman (3-7) have shown that, in syngeneic rodent systems, the circulating factors responsible for such resistance are inhibitors of angiogenesis. Two of these have been identified: angiostatin and endostatin. In these model systems, primary tumors secrete inducers of angiogenesis and also generate inhibitors of angiogenesis. In the microenvironment of the large primary tumor, the inducers are apparently sufficient to overcome the effects of the inhibitors because the new vessels essential for progressive tumor growth are present. However, when inducers and inhibitors are shed from the tumor bed into the circulation, levels of the more labile inducers fall off rapidly whereas levels of the more stable inhibitors rise, creating a systemic antiangiogenic environment that prevents small nests of metastatic cells from inducing neovascularization. As a result, these incipient tumors remain small and dormant. On removal of the primary tumor, inhibitor levels fall and the previously dormant metastases expand vigorously.Concomitant tumor resistance likely also occurs in human cancer patients. There are a variety of anecdotal clinical reports in the literature describing the fast and disastrous development of what must have been preexisting metastases following surgical removal of a primary tumor, (for example, see ref. 8 and citations in refs. 1 and 2). One such case is that of the patient from whom the widely used human fibrosarcoma line HT1080 was derived and who d...