PMID- 21597001
OWN - NLM
STAT- MEDLINE
DCOM- 20110826
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 108
IP  - 23
DP  - 2011 Jun 7
TI  - Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A 
      in stromal perivascular cells.
PG  - 9589-94
LID - 10.1073/pnas.1017945108 [doi]
AB  - 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.
FAU - Chen, Weiwei
AU  - Chen W
AD  - Department of Pathology, Genentech, Inc., San Francisco, CA 94080, USA.
FAU - Tang, Tracy
AU  - Tang T
FAU - Eastham-Anderson, Jeff
AU  - Eastham-Anderson J
FAU - Dunlap, Debra
AU  - Dunlap D
FAU - Alicke, Bruno
AU  - Alicke B
FAU - Nannini, Michelle
AU  - Nannini M
FAU - Gould, Stephen
AU  - Gould S
FAU - Yauch, Robert
AU  - Yauch R
FAU - Modrusan, Zora
AU  - Modrusan Z
FAU - DuPree, Kelly J
AU  - DuPree KJ
FAU - Darbonne, Walter C
AU  - Darbonne WC
FAU - Plowman, Greg
AU  - Plowman G
FAU - de Sauvage, Frederic J
AU  - de Sauvage FJ
FAU - Callahan, Christopher A
AU  - Callahan CA
LA  - eng
SI  - GEO/GSE29316
PT  - Journal Article
DEP - 20110519
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Patched Receptors)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Culture
MH  - Endothelial Cells/cytology/metabolism
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Hedgehog Proteins/*genetics
MH  - Mice
MH  - Mice, Nude
MH  - Myofibroblasts/cytology/metabolism
MH  - Neoplasms/blood supply/*genetics/pathology
MH  - Neoplasms, Experimental/blood supply/genetics/pathology
MH  - Neovascularization, Pathologic/*genetics
MH  - Neovascularization, Physiologic/genetics
MH  - Oligonucleotide Array Sequence Analysis
MH  - Patched Receptors
MH  - Receptors, Cell Surface/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*genetics
MH  - Stromal Cells/metabolism/pathology
MH  - Transplantation, Heterologous
MH  - Vascular Endothelial Growth Factor A/*genetics
PMC - PMC3111273
COIS- Conflict of interest statement: All authors are employees of Genentech, Inc., a 
      wholly owned subsidiary of F. Hoffmann-La Roche Ltd., and may own equity in 
      Roche.
EDAT- 2011/05/21 06:00
MHDA- 2011/08/30 06:00
PMCR- 2011/05/19
CRDT- 2011/05/21 06:00
PHST- 2011/05/21 06:00 [entrez]
PHST- 2011/05/21 06:00 [pubmed]
PHST- 2011/08/30 06:00 [medline]
PHST- 2011/05/19 00:00 [pmc-release]
AID - 1017945108 [pii]
AID - 201017945 [pii]
AID - 10.1073/pnas.1017945108 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9589-94. doi: 
      10.1073/pnas.1017945108. Epub 2011 May 19.