title: Invading cancer cells are predominantly in G0/G1 resulting in chemoresistance demonstrated by real-time FUCCI imaging.
abstract: Invasive cancer cells are a critical target in order to prevent metastasis. In the present report, we demonstrate real-time visualization of cell cycle kinetics of invading cancer cells in 3-dimensional (3D) Gelfoam® histoculture, which is in vivo-like. A fluorescence ubiquitination cell cycle indicator (FUCCI) whereby G0/G1 cells express a red fluorescent protein and S/G2/M cells express a green fluorescent protein was used to determine the cell cycle position of invading and non-invading cells. With FUCCI 3D confocal imaging, we observed that cancer cells in G0/G1 phase in Gelfoam® histoculture migrated more rapidly and further than cancer cells in S/G2/M phases. Cancer cells ceased migrating when they entered S/G2/M phases and restarted migrating after cell division when the cells re-entered G0/G1. Migrating cancer cells also were resistant to cytotoxic chemotherapy, since they were preponderantly in G0/G1, where cytotoxic chemotherapy is not effective. The results of the present report suggest that novel therapy targeting G0/G1 cancer cells should be developed to prevent metastasis.
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; San Diego, 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; Department of Surgery; University of California, San Diego; San Diego, 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; San Diego, CA USA.
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Mii
authors.affiliation: AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; San Diego, 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; San Diego, 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; San Diego, CA USA.
authors.forename: Mako
authors.initials: M
authors.lastname: Yamamoto
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: Department of Surgery; University of California, San Diego; San Diego, 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; San Diego, CA USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D005781:Gelatin Sponge, Absorbable; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D016192:Resting Phase, Cell Cycle / Q000502:physiology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000097573:Red Fluorescent Protein
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein
keywords: 3D; FUCCI; Gelfoam histoculture; cancer invasion; cell cycle kinetics; confocal laser microscopy; fluorescent proteins; real-time imaging