title: Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner.
abstract: Whereas the roles of proangiogenic factors in carcinogenesis are well established, those of endogenous angiogenesis inhibitors (EAIs) remain to be fully elaborated. We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis.
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Michael B
authors.initials: MB
authors.lastname: Duncan
authors.forename: Jessica
authors.initials: J
authors.lastname: Pahler
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Margot
authors.initials: M
authors.lastname: Martino
authors.forename: Julie
authors.initials: J
authors.lastname: Lively
authors.forename: Thomas
authors.initials: T
authors.lastname: Mundel
authors.forename: Mary
authors.initials: M
authors.lastname: Soubasakos
authors.forename: Kristofer
authors.initials: K
authors.lastname: Rubin
authors.forename: Takaaki
authors.initials: T
authors.lastname: Takeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D043169:Endostatins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D010455:Peptides / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D016019:Survival Analysis; D019700:Thrombospondin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C477639:3-(5-methyl-2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl)propionic acid; D001324:Autoantigens; D024141:Collagen Type IV; D043169:Endostatins; D007211:Indoles; D010455:Peptides; D011422:Propionates; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C057112:type IV collagen alpha3 chain