CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells

  • Authors:
    • Eriko Katsuta
    • Shinji Tanaka
    • Kaoru Mogushi
    • Shu Shimada
    • Yoshimitsu Akiyama
    • Arihiro Aihara
    • Satoshi Matsumura
    • Yusuke Mitsunori
    • Daisuke Ban
    • Takanori Ochiai
    • Atsushi Kudo
    • Hiroshi Fukamachi
    • Hiroshi Tanaka
    • Koh Nakayama
    • Shigeki Arii
    • Minoru Tanabe
  • View Affiliations

  • Published online on: December 18, 2015     https://doi.org/10.3892/ijo.2015.3299
  • Pages: 657-669
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Abstract

Identification and purification of cancer stem cells (CSCs) lead to the discovery of novel therapeutic targets; however, there has been no study on isolation of the CSC population among pancreatic neuroendocrine tumors (pNETs). This study aimed to identify pNET CSCs and to characterize a therapeutic candidate for pNET CSCs. We identified CSCs by aldehyde dehydrogenase (ALDH) activity in pNET clinical specimens and cell lines. We verified whether or not these cells have the stemness property in vivo and in vitro. ALDHhigh cells, but not control bulk cells, formed spheres, proliferated under hypoxic condition as well as normoxic condition and promoted cell motility, which are features of CSCs. Injection of as few as 10 ALDHhigh cells led to subcutaneous tumor formation, and 105 ALDHhigh cells, but not control bulk cells, established metastases in mice. Comprehensive gene expression analysis revealed that genes associated with mesenchymal stem cells, including CD73, were overexpressed in ALDHhigh cells. Additionally, the in vitro and in vivo effects of an inhibitor of CD73 were investigated. The CD73 inhibitor APCP significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumor growth observed for ALDHhigh cells. Finally, its expression was evaluated using clinical pNET tissue samples. Immunohistochemical analysis of clinical tissue samples demonstrated CD73 expression was significantly correlated with the invasion into adjacent organs. Since recent studies revealed CD73 as a potential biomarker of anti-PD-1 immune checkpoint therapy, CD73 might be a promising therapeutic target for pNET CSCs.
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February 2016
Volume 48 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Katsuta, E., Tanaka, S., Mogushi, K., Shimada, S., Akiyama, Y., Aihara, A. ... Tanabe, M. (2016). CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells. International Journal of Oncology, 48, 657-669. https://doi.org/10.3892/ijo.2015.3299
MLA
Katsuta, E., Tanaka, S., Mogushi, K., Shimada, S., Akiyama, Y., Aihara, A., Matsumura, S., Mitsunori, Y., Ban, D., Ochiai, T., Kudo, A., Fukamachi, H., Tanaka, H., Nakayama, K., Arii, S., Tanabe, M."CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells". International Journal of Oncology 48.2 (2016): 657-669.
Chicago
Katsuta, E., Tanaka, S., Mogushi, K., Shimada, S., Akiyama, Y., Aihara, A., Matsumura, S., Mitsunori, Y., Ban, D., Ochiai, T., Kudo, A., Fukamachi, H., Tanaka, H., Nakayama, K., Arii, S., Tanabe, M."CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells". International Journal of Oncology 48, no. 2 (2016): 657-669. https://doi.org/10.3892/ijo.2015.3299