CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 c ells, b ut n ot c ontrol 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.

Original languageEnglish
Pages (from-to)657-669
Number of pages13
JournalInternational journal of oncology
Volume48
Issue number2
DOIs
Publication statusPublished - 2016 Feb

Keywords

  • CD73
  • Cancer stem cell
  • Immune checkpoint
  • Molecular target
  • PD-1
  • Pancreatic neuroendocrine tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    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. (2016). CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells. International journal of oncology, 48(2), 657-669. https://doi.org/10.3892/ijo.2015.3299