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Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
Published on: June 20, 2015
CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells
Eriko Katsuta1, Shinji Tanaka1, Kaoru Mogushi2
1Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
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.
Insights
Researchers identified cancer stem cells (CSCs) in pancreatic neuroendocrine tumors (pNETs) using aldehyde dehydrogenase (ALDH) activity. Targeting CD73, overexpressed in these pNET CSCs, reduced tumor growth and metastasis, suggesting a novel therapeutic strategy.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Biochemistry
Background:
- Cancer stem cells (CSCs) are crucial for tumor initiation, progression, and therapeutic resistance.
- Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms, and their CSC population remains poorly understood.
- Identifying CSCs in pNETs is essential for developing targeted therapies.
Purpose of the Study:
- To identify and isolate cancer stem cells (CSCs) within pancreatic neuroendocrine tumors (pNETs).
- To characterize the stemness properties of pNET CSCs in vitro and in vivo.
- To evaluate CD73 as a potential therapeutic target for pNET CSCs.
Main Methods:
- CSCs were identified and isolated from pNET specimens and cell lines based on high aldehyde dehydrogenase (ALDH) activity.
- Stemness properties (sphere formation, proliferation, motility) were assessed in vitro and tumorigenicity/metastasis in vivo.
- Gene expression analysis identified overexpressed genes in ALDHhigh cells, including CD73.
- The efficacy of a CD73 inhibitor (APCP) was evaluated in vitro and in vivo.
- CD73 expression was analyzed in clinical pNET samples via immunohistochemistry.
Main Results:
- ALDHhigh cells exhibited CSC characteristics, including sphere formation, proliferation under varying oxygen conditions, and enhanced motility.
- A low number of ALDHhigh cells (10) formed tumors, and a larger number (105) induced metastasis in mice.
- Genes associated with mesenchymal stem cells, notably CD73, were significantly overexpressed in ALDHhigh cells.
- The CD73 inhibitor APCP suppressed sphere formation, motility, and tumor growth of ALDHhigh cells.
- Clinical pNET samples showed that CD73 expression correlates with invasion into adjacent organs.
Conclusions:
- Aldehyde dehydrogenase (ALDH) activity effectively identifies cancer stem cells (CSCs) in pancreatic neuroendocrine tumors (pNETs).
- CD73 is overexpressed in pNET CSCs and represents a promising therapeutic target, as its inhibition reduces tumor progression and metastasis.
- CD73's correlation with invasion and potential role in immune checkpoint therapy warrants further investigation for pNET treatment strategies.
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