Antiangiogenic domains shared by thrombospondins and metallospondins, a new family of angiogenic inhibitors

The growth of solid tumors has been shown to depend on neovascularization. By understanding the mechanisms that control the neovascular response, it may be possible to design therapeutic strategies to selectively prevent or halt pathologic vascular growth and restrain cancer progression. Thrombospondin-1 is an extracellular matrix protein that among several functions suppresses capillary growth in angiogenesis assays. We have demonstrated that within the context of the mammary gland TSP1 can modulate normal development of blood vessels. Expression of TSP1 in transgenic animals under the control of the MMTV promoter was associated with a 50-72% reduction in capillary growth. In addition, TSP1 reduced tumor size in transgenic overexpressors. The data suggest an important role for TSP1 in modulating vascular growth in both normal and pathologic tissues. The antiangiogenic region of TSP1 has been mapped to the type I (properdin) repeats. To identify novel proteins with such a domain, we have cloned two cDNAs (METH-1 and METH-2) which also have antiangiogenic properties. In addition to carboxyterminal thrombospondin-like domains they also contain metalloproteinase and disintegrin sequences. Expression of both proteins is broad but nonoverlapping. Recombinant fragments from these sequences have strong antiangiogenic potential in the CAM and cornea pocket assays. At the same molar ratio, METH-1 and METH-2 are about 20-fold more potent than TSP1. We predict that these proteins are likely endogenous modulators of vascular growth with relevant therapeutic potential in cancer and other disease states.