Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells
Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells
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DOI：
10.1111/j.1349-7006.2008.00795.x
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发表时间：
2008-06-01
期刊：
影响因子：
5.7
通讯作者：
Kohgo, Yutaka
中科院分区：
文献类型：
--
作者：
Yamazaki, Madoka;Nakamura, Kazumasa;Kohgo, Yutaka
Hedgehog信号转导在胰腺癌的发病机制中是重要的。最近的一些观察表明，在出生后的新生血管的音刺猬（SHH）的参与。我们确定了SHH在胰腺癌肿瘤相关血管生成中的新作用。免疫组织化学分析显示，修补同源物1（PTCH 1），刺猬信号的受体和转录靶点，在胰腺癌内的内皮细胞的一小部分中表达，但在正常胰腺组织中没有。当从人外周血分离的内皮祖细胞（EPC）与来自SHH转染的293细胞或胰腺癌细胞的上清液一起培养时，血管内皮生长因子（VEGF）、基质细胞衍生因子-1和血管生成素-1的mRNA水平显著增加，而在人脐静脉内皮细胞（HUVEC）和人真皮微血管内皮细胞（HMVEC）中未观察到这种诱导作用。内皮祖细胞与内皮祖细胞共培养可促进HUVEC小管形成，高表达SHH的KP-1 N胰腺癌细胞培养上清预处理内皮祖细胞可显著增强内皮祖细胞的这种作用。通过用环巴胺或中和抗体特异性抑制SHH，该作用部分减弱。这些研究结果表明，肿瘤源性SHH可以诱导血管生成，这是通过其对EPC的特异性作用介导的。靶向SHH将是一种新的治疗方法，不仅可以抑制癌细胞的增殖，而且可以抑制EPC介导的血管生成。
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.