title: Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors.
abstract: 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.
authors.affiliation: Center for Matrix Biology, Department of Medicine, and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hamano
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Akulapalli
authors.initials: A
authors.lastname: Sudhakar
authors.forename: Mary
authors.initials: M
authors.lastname: Soubasakos
authors.forename: Udaya
authors.initials: U
authors.lastname: Yerramalla
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Mark
authors.initials: M
authors.lastname: Kieran
authors.forename: Amish
authors.initials: A
authors.lastname: Shah
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D020533:Angiogenesis Inhibitors / Q000502:physiology*; D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000096:biosynthesis / Q000502:physiology*; D043170:Collagen Type XVIII / Q000096:biosynthesis; D043169:Endostatins / Q000502:physiology*; D039661:Integrin beta3 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D019700:Thrombospondin 1 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D001324:Autoantigens; D024141:Collagen Type IV; D043170:Collagen Type XVIII; D043169:Endostatins; D039661:Integrin beta3; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins; C057112:type IV collagen alpha3 chain