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Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells
- Source :
- Cancer Science. 99:1131-1138
- Publication Year :
- 2008
- Publisher :
- Wiley, 2008.
-
Abstract
- Hedgehog signaling is important in the pathogenesis of pancreatic cancer. Several recent observations suggest the involvement of sonic hedgehog (SHH) in postnatal neovascularization. We identified a novel role for SHH in tumor-associated angiogenesis in pancreatic cancer. Immunohistochemical analysis revealed that patched homolog 1 (PTCH1), both a receptor for and transcriptional target of hedgehog signaling, was expressed in a small fraction of endothelial cells within pancreatic cancer, but not in normal pancreatic tissue. When endothelial progenitor cells (EPC) isolated from human peripheral blood were cultured with supernatant from SHH-transfected 293 cells or pancreatic cancer cells, mRNA levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and angiopoietin-1 were significantly increased, whereas no such induction was observed in human umbilical vein endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMVEC). HUVEC tube formation was stimulated when cocultured with EPC, and preconditioning EPC with supernatant from KP-1 N pancreatic cancer cells highly expressing SHH significantly enhanced the effect. The effect was partially attenuated by specific inhibition of SHH with cyclopamine or a neutralizing antibody. These findings suggest that tumor-derived SHH can induce angiogenesis, and this is mediated by its effects on EPC specifically. Targeting SHH would be a novel therapeutic approach that can inhibit not only proliferation of cancer cells but also EPC-mediated angiogenesis.
- Subjects :
- Male
Vascular Endothelial Growth Factor A
Umbilical Veins
Cancer Research
Angiogenesis
Fluorescent Antibody Technique
chemistry.chemical_compound
Sonic hedgehog
Cells, Cultured
Neovascularization, Pathologic
Reverse Transcriptase Polymerase Chain Reaction
Stem Cells
Veratrum Alkaloids
学位授与年月日:平成20年9月30日
Dermis
General Medicine
Hedgehog signaling pathway
Patched-1 Receptor
Vascular endothelial growth factor
Endothelial stem cell
Vascular endothelial growth factor A
Oncology
embryonic structures
cardiovascular system
Female
Human umbilical vein endothelial cell
Carcinoma, Pancreatic Ductal
Signal Transduction
Patched Receptors
medicine.medical_specialty
animal structures
Cyclopamine
Blotting, Western
Receptors, Cell Surface
Biology
Internal medicine
Angiopoietin-1
medicine
Humans
Hedgehog Proteins
RNA, Messenger
Aged
Chemokine CXCL12
Pancreatic Neoplasms
Endocrinology
chemistry
旭川医科大学:博士(医学)(乙第412号)
Cancer research
biology.protein
Endothelium, Vascular
Subjects
Details
- ISSN :
- 13497006 and 13479032
- Volume :
- 99
- Database :
- OpenAIRE
- Journal :
- Cancer Science
- Accession number :
- edsair.doi.dedup.....32bfac3210972984c2d7299c94e0ede2