Open AccessSonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells
Author(s) -
Yamazaki Madoka,
Nakamura Kazumasa,
Mizukami Yusuke,
Ii Masaaki,
Sasajima Junpei,
Sugiyama Yoshiaki,
Nishikawa Tomoya,
Nakano Yasuhiro,
Yanagawa Nobuyuki,
Sato Kazuya,
Maemoto Atsuo,
Tanno Satoshi,
Okumura Toshikatsu,
Karasaki Hidenori,
Kono Toru,
Fujiya Mikihiro,
Ashida Toshifumi,
Chung Daniel C.,
Kohgo Yutaka
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00795.x
Subject(s) - sonic hedgehog , cyclopamine , pancreatic cancer , angiogenesis , cancer research , progenitor cell , stromal cell , patched , endothelial stem cell , gli1 , cancer cell , biology , hedgehog signaling pathway , vascular endothelial growth factor , cancer , microbiology and biotechnology , medicine , stem cell , signal transduction , in vitro , biochemistry , vegf receptors
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. ( Cancer Sci 2008; 99: 1131–1138)