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Cancer science
Dec, 2023;114 (12): 4571-4582.

Dual role of autotaxin as novel biomarker and therapeutic target in pancreatic neuroendocrine neoplasms.

Tadashi Toyohara, Michihiro Yoshida, Katsuyuki Miyabe, Kazuki Hayashi, Itaru Naitoh, Hiromu Kondo, Yasuki Hori, Akihisa Kato, Kenta Kachi, Go Asano, Hidenori Sahashi, Akihisa Adachi, Kayoko Kuno, Yusuke Kito, Yoichi Matsuo, Hiromi Kataoka
Author Information
  1. Tadashi Toyohara: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ORCID
  2. Michihiro Yoshida: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ORCID
  3. Katsuyuki Miyabe: Department of Gastroenterology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan. ORCID
  4. Kazuki Hayashi: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  5. Itaru Naitoh: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  6. Hiromu Kondo: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  7. Yasuki Hori: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  8. Akihisa Kato: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ORCID
  9. Kenta Kachi: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  10. Go Asano: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  11. Hidenori Sahashi: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  12. Akihisa Adachi: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  13. Kayoko Kuno: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  14. Yusuke Kito: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  15. Yoichi Matsuo: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ORCID
  16. Hiromi Kataoka: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ORCID
PMID: 37770812 DOI: 10.1111/cas.15980

Abstract

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target.

Keywords

autotaxin biomarker lysophosphatidic acid molecular target therapy neuroendocrine tumor

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Grants

  1. 21K20844/Japan Society for the Promotion of Science
  2. 23K07444/Japan Society for the Promotion of Science
  3. N/A/Pancreas Research Foundation of Japan

MeSH Term

Animals
Humans
Mice
Biomarkers
Cell Line
Disease Models, Animal
Neuroendocrine Tumors
Pancreatic Neoplasms
Phosphoric Diester Hydrolases
RNA Interference

Chemicals

Biomarkers
Phosphoric Diester Hydrolases
alkylglycerophosphoethanolamine phosphodiesterase
Journal Article

Word Cloud

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