title: Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast.
abstract: Despite strong possibility that endothelial cells (ECs) of tumors and normal tissues may differ in various aspects, most previous studies on ECs have used normal cells. Here, we purified ECs from tumorous and normal human breast tissues, and studied the effect of radiation on angiogenesis and relevant molecular mechanisms in these cells. We found that in normal tissue-derived ECs (NECs), 4 Gy irradiation increased tube formation, matrix metalloproteinase 2 (MMP-2) expression and extracellular signal-regulated kinase (ERK) pathway activation. In cancer-derived ECs (CECs), however, 4 Gy irradiation significantly reduced tube formation, increased the production of angiostatin and interleukin-6 (IL-6), and upregulated AKT and c-Jun N-terminal kinase (JNK) pathway activation. Knockdown experiments showed that siMMP-2 efficiently inhibited tube formation by irradiated NECs, whereas siPlasminogen effectively attenuated the radiation-induced suppression of tube formation and the upregulation of angiostatin in CECs. Moreover, siIL-6 clearly inhibited the radiation-induced generation of angiostatin in CECs. Inhibition of ERK with a pharmacological inhibitor or small interfering RNAs (siRNAs) markedly suppressed the radiation-induced tube formation and MMP-2 upregulation in NECs, whereas the inhibition of either AKT or JNK with pharmacological inhibitor or siRNA treatment of CECs markedly attenuated the inhibition of tube formation and the upregulation of angiostatin and IL-6 caused by 4 Gy irradiation. These observations collectively demonstrate that there are distinct differences in the radiation responses of NECs and CECs, and might provide important clues for improving the efficacy of radiation therapy.
authors.affiliation: Department of Microbiology, Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: E-T
authors.initials: ET
authors.lastname: Oh
authors.affiliation: Department of Microbiology, Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: M-T
authors.initials: MT
authors.lastname: Park
authors.affiliation: Department of Microbiology, Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Song
authors.affiliation: Department of Microbiology, Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Surgery, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Y U
authors.initials: YU
authors.lastname: Cho
authors.affiliation: Department of Surgery, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chu
authors.affiliation: Department of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
authors.forename: E K
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Department of Microbiology, Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
mesh_terms: D043168:Angiostatins / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D042783:Endothelial Cells / Q000502:physiology / Q000528:radiation effects*; D005260:Female; D015870:Gene Expression / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D043168:Angiostatins; D010958:Plasminogen; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2