Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells.
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.
Yamazaki
Madoka
M
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical College, Hokkaido 078-8510, Japan.
Nakamura
Kazumasa
K
Mizukami
Yusuke
Y
Ii
Masaaki
M
Sasajima
Junpei
J
Sugiyama
Yoshiaki
Y
Nishikawa
Tomoya
T
Nakano
Yasuhiro
Y
Yanagawa
Nobuyuki
N
Sato
Kazuya
K
Maemoto
Atsuo
A
Tanno
Satoshi
S
Okumura
Toshikatsu
T
Karasaki
Hidenori
H
Kono
Toru
T
Fujiya
Mikihiro
M
Ashida
Toshifumi
T
Chung
Daniel C
DC
Kohgo
Yutaka
Y
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
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