title: Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells.
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.
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical College, Hokkaido 078-8510, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Junpei
authors.initials: J
authors.lastname: Sasajima
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakano
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagawa
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sato
authors.forename: Atsuo
authors.initials: A
authors.lastname: Maemoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanno
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Okumura
authors.forename: Hidenori
authors.initials: H
authors.lastname: Karasaki
authors.forename: Toru
authors.initials: T
authors.lastname: Kono
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Fujiya
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ashida
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000368:Aged; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply* / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D014471:Umbilical Veins / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: D042683:Angiopoietin-1; D054377:Chemokine CXCL12; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014704:Veratrum Alkaloids; C000541:cyclopamine