title: Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness.
abstract: The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G₀/G₁ and 70% in S/G₂/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G₀/G₁ phase. Similarly, approximately 75% of cancer cells far from (> 100 µm) tumor blood vessels of an established tumor are in G₀/G₁. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G₂/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA; 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: AntiCancer, Inc; San Diego, CA USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tome
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Fuminari
authors.initials: F
authors.lastname: Uehara
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Mako
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suetsugu
authors.affiliation: 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: Center for Innovative Clinical Medicine; Okayama University Hospital; Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.affiliation: AntiCancer, Inc; San Diego, CA USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: 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: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D061848:Optical Imaging; D017239:Paclitaxel / Q000494:pharmacology; D062211:Spatio-Temporal Analysis
chemical_list: D000970:Antineoplastic Agents; D017239:Paclitaxel; D002945:Cisplatin
keywords: FUCCI; cell cycle; confocal laser microscopy; dormancy; drug resistance; fluorescent proteins; tumor; tumor blood vessels