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
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
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Research Article Oncology

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

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

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Figure 6

CD13 inhibition elicits cancer regression in vivo.

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CD13 inhibition elicits cancer regression in vivo. (A) HuH7-xenografted ...
(A) HuH7-xenografted mice were treated with 5-FU or ubenimex for 3 days. The sections were stained with anti-human CD13 (red), Ki-67 (green), and DAPI (blue). Each right-hand panel shows a high magnification (×20, control and 5-FU; ×40, Ube) of the white dot square on the left (×10, control and 5-FU; ×20, Ube). White arrows: cellular clusters express CD13 but not Ki-67 (upper panels), residual Ki-67+ cancer cells (middle panels), and a residual CD13+ cell (lower panels). (B) PLC/PRF/5-xenografted mice were treated with 5-FU, ubenimex, and ubenimex plus 5-FU for 14 days. The black arrows indicate a small amount of residual cancer. The sections were stained with H&E (×10), anti-human CD13 (red), anti-human CD90 (green), and DAPI (blue) (×20, control, 5-FU, and Ube; ×40, Ube + 5-FU). Nonspecific and fragmented expression of CD13 (white arrow). In situ hybridization for DNA fragmentation (low and high magnification). Black dot-like structures indicate labeled DNA. (C) Tumors of control and ubenimex–plus–5-FU–treated mice. Black arrowheads indicate the tumor margin. (D) The relative tumor volumes (after treatment [mm3]/before treatment [mm3] × 100%) of the control, 5-FU, ubenimex, and ubenimex–plus–5-FU–treated mice. Data represent mean ± SD from independent experiments. *NS; **P < 0.01. (E) The CD13+ cell–enriched fractions obtained from 5-FU–treated mice were serially transplanted into secondary NOD/SCID mice. The mice were treated with ubenimex (Ube; n = 6) or received no treatment (control; n = 10) from the day after transplantation for 7 days. Tumor growth was observed for 3 weeks.