title: Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging.
abstract: We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G2phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.|b Department of Surgery , University of California San Diego , CA , USA.|c Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.|b Department of Surgery , University of California San Diego , CA , USA.|c Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Takehara
authors.affiliation: d Center for Innovative Clinical Medicine, Okayama University Hospital , Okayama , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.affiliation: c Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: e Oncolys Biopharma, Inc. , Tokyo , Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.affiliation: c Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.affiliation: c Department of Gastroenterological Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.|b Department of Surgery , University of California San Diego , CA , USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003199:Computer Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005453:Fluorescence; D006801:Humans; D021621:Imaging, Three-Dimensional; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents
keywords: FUCCI; angiogenesis; cell cycle; chemotherapy; decoy; imaging; quiescence; resistance