Disruption of the systemic angiogenesis balance to favor enhanced angiogenesis is speculated to represent a key step in the growth of
tumors. Although a major emphasis has been placed on the increase of
angiogenesis stimulators, such as
VEGF, on the disruption of the angiogenic balance, the potential role of the physiological levels of endogenous inhibitors of angiogenesis on
tumor growth is poorly understood. Here, we use three independent lines of mice deficient in
tumstatin,
endostatin, or thrombospondin-1 (TSP-1), to address the role that these endogenous
angiogenesis inhibitors play in
tumor growth. Our experiments demonstrate that normal physiological levels of these inhibitors serve to retard the growth of
tumors, and that their absence leads to enhanced angiogenesis and a 2- to 3-fold increase in
tumor growth. The
tumor-suppressive action of
TSP-1,
endostatin, and
tumstatin correlates with expression of CD36 receptor,
alpha5beta1 integrin, and
alphavbeta3 integrin on proliferating endothelial cells, respectively. Moreover,
tumors grow 2-fold faster in the
tumstatin/TSP-1 double-knockout mice, compared with either the
tumstatin- or the TSP-1-deficient mice, strongly suggesting that ceiling rate of
cancer growth is not completely dependent on the genetic defects of
cancer cells but also depends on the host-derived tumor microenvironment. Additionally,
tumor growth in transgenic mice overproducing
endostatin specifically in the endothelial cells (a 1.6-fold increase in the circulating levels; mimicking
Down's syndrome condition) is 3-fold slower than the
tumor growth in wild-type mice. Collectively, our data suggest that physiological levels of endogenous inhibitors of angiogenesis can serve as endothelium-specific
tumor suppressors.