title: Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance.
abstract: Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance. Cancer Res; 76(11); 3200-10. ©2016 AACR.
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. ntakaku@biken.osaka-u.ac.jp naitohi@biken.osaka-u.ac.jp.
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Naito
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kidoya
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Muramatsu
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takara
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Eino
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamane
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iba
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. ntakaku@biken.osaka-u.ac.jp naitohi@biken.osaka-u.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D058985:Side-Population Cells / Q000187:drug effects / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors