title: Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells.
abstract: Hedgehog (Hh) signaling is critical to the patterning and development of a variety of organ systems, and both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligands, activation occurs within the stromal microenvironment. Testing whether ligand-driven Hh signaling promotes tumor angiogenesis, we found that Hh antagonism reduced the vascular density of Hh-producing LS180 and SW480 xenografts. In addition, ectopic expression of sonic hedgehog in low-Hh-expressing DLD-1 xenografts increased tumor vascular density, augmented angiogenesis, and was associated with canonical Hh signaling within perivascular tumor stromal cells. To better understand the molecular mechanisms underlying Hh-mediated tumor angiogenesis, we established an Hh-sensitive angiogenesis coculture assay and found that fibroblast cell lines derived from a variety of human tissues were Hh responsive and promoted angiogenesis in vitro through a secreted paracrine signal(s). Affymetrix array analyses of cultured fibroblasts identified VEGF-A, hepatocyte growth factor, and PDGF-C as candidate secreted proangiogenic factors induced by Hh stimulation. Expression studies of xenografts and angiogenesis assays using combinations of Hh and VEGF-A inhibitors showed that it is primarily Hh-induced VEGF-A that promotes angiogenesis in vitro and augments tumor-derived VEGF to promote angiogenesis in vivo.
authors: Department of Pathology, Genentech, Inc., San Francisco, CA 94080, USA.
authors: Weiwei
authors: W
authors: Chen
authors: Tracy
authors: T
authors: Tang
authors: Jeff
authors: J
authors: Eastham-Anderson
authors: Debra
authors: D
authors: Dunlap
authors: Bruno
authors: B
authors: Alicke
authors: Michelle
authors: M
authors: Nannini
authors: Stephen
authors: S
authors: Gould
authors: Robert
authors: R
authors: Yauch
authors: Zora
authors: Z
authors: Modrusan
authors: Kelly J
authors: KJ
authors: DuPree
authors: Walter C
authors: WC
authors: Darbonne
authors: Greg
authors: G
authors: Plowman
authors: Frederic J
authors: FJ
authors: de Sauvage
authors: Christopher A
authors: CA
authors: Callahan
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