Department of Molecular, Cell and Developmental Biology and Molecular Biology Institute, University of California, Los Angeles, California 90095, USA
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.
