CD13 is a therapeutic target in human liver cancer stem cells

Naotsugu Haraguchi, Hideshi Ishii, Koshi Mimori, Fumiaki Tanaka, Masahisa Ohkuma, Ho Min Kim, Hirofumi Akita, Daisuke Takiuchi, Hisanori Hatano, Hiroaki Nagano, Graham F. Barnard, Yuichiro Doki, Masaki Mori

Research output: Contribution to journalArticle

370 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3326-3339
Number of pages14
JournalJournal of Clinical Investigation
Volume120
Issue number9
DOIs
Publication statusPublished - Sep 1 2010

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Neoplastic Stem Cells
Liver Neoplasms
Neoplasms
Fluorouracil
Therapeutics
Radiotherapy
Recurrence
Cell Cycle Resting Phase
Tumor Burden
Heterografts
DNA Damage
Capsules
Cell Cycle
Radiation
Apoptosis
Cell Line

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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CD13 is a therapeutic target in human liver cancer stem cells. / Haraguchi, Naotsugu; Ishii, Hideshi; Mimori, Koshi; Tanaka, Fumiaki; Ohkuma, Masahisa; Kim, Ho Min; Akita, Hirofumi; Takiuchi, Daisuke; Hatano, Hisanori; Nagano, Hiroaki; Barnard, Graham F.; Doki, Yuichiro; Mori, Masaki.

In: Journal of Clinical Investigation, Vol. 120, No. 9, 01.09.2010, p. 3326-3339.

Research output: Contribution to journalArticle

Haraguchi, N, Ishii, H, Mimori, K, Tanaka, F, Ohkuma, M, Kim, HM, Akita, H, Takiuchi, D, Hatano, H, Nagano, H, Barnard, GF, Doki, Y & Mori, M 2010, 'CD13 is a therapeutic target in human liver cancer stem cells', Journal of Clinical Investigation, vol. 120, no. 9, pp. 3326-3339. https://doi.org/10.1172/JCI42550
Haraguchi, Naotsugu ; Ishii, Hideshi ; Mimori, Koshi ; Tanaka, Fumiaki ; Ohkuma, Masahisa ; Kim, Ho Min ; Akita, Hirofumi ; Takiuchi, Daisuke ; Hatano, Hisanori ; Nagano, Hiroaki ; Barnard, Graham F. ; Doki, Yuichiro ; Mori, Masaki. / CD13 is a therapeutic target in human liver cancer stem cells. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 9. pp. 3326-3339.
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