title: CD13 is a therapeutic target in human liver cancer stem cells.
abstract: Cancer stem cells (CSCs) are generally dormant or slowly cycling tumor cells that have the ability to reconstitute tumors. They are thought to be involved in tumor resistance to chemo/radiation therapy and tumor relapse and progression. However, neither their existence nor their identity within many cancers has been well defined. Here, we have demonstrated that CD13 is a marker for semiquiescent CSCs in human liver cancer cell lines and clinical samples and that targeting these cells might provide a way to treat this disease. CD13+ cells predominated in the G0 phase of the cell cycle and typically formed cellular clusters in cancer foci. Following treatment, these cells survived and were enriched along the fibrous capsule where liver cancers usually relapse. Mechanistically, CD13 reduced ROS-induced DNA damage after genotoxic chemo/radiation stress and protected cells from apoptosis. In mouse xenograft models, combination of a CD13 inhibitor and the genotoxic chemotherapeutic fluorouracil (5-FU) drastically reduced tumor volume compared with either agent alone. 5-FU inhibited CD90+ proliferating CSCs, some of which produce CD13+ semiquiescent CSCs, while CD13 inhibition suppressed the self-renewing and tumor-initiating ability of dormant CSCs. Therefore, combining a CD13 inhibitor with a ROS-inducing chemo/radiation therapy may improve the treatment of liver cancer.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Haraguchi
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Masahisa
authors.initials: M
authors.lastname: Ohkuma
authors.forename: Ho Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takiuchi
authors.forename: Hisanori
authors.initials: H
authors.lastname: Hatano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Graham F
authors.initials: GF
authors.lastname: Barnard
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018826:CD13 Antigens; D005472:Fluorouracil