Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Gastroenterology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan.
Cancer Sci. 2023 Dec;114(12):4571-4582. doi: 10.1111/cas.15980. Epub 2023 Sep 28.
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.
胰腺神经内分泌肿瘤（panNENs）是罕见的胰腺肿瘤，其治疗描述仍然有限。自分泌运动因子（ATX）是一种分泌的自分泌运动因子，参与溶血磷脂酸（LPA）的产生，LPA 是一种脂质介质，可促进各种癌症的进展。本研究旨在阐明 ATX-LPA 轴在 panNENs 中的重要性，并使用临床数据、细胞系和小鼠模型证实其对 panNEN 进展的贡献。panNEN 患者的血清 ATX 水平高于其他胰腺疾病（慢性胰腺炎、胰腺导管腺癌 [PDAC]、导管内乳头状黏液性肿瘤、自身免疫性胰腺炎）和健康对照者，并且 61%的临床标本强烈染色 ATX。在我们遇到的一个病例中，血清 ATX 水平随疾病进展而波动。体外研究表明，panNEN 细胞系中的 ATX mRNA 表达高于 PDAC 细胞系。panNEN 细胞系中的细胞增殖和迁移通过 ATX-LPA 轴被刺激，并通过 RNA 干扰或抑制剂被抑制。体内研究表明，ATX 抑制剂 GLPG1690 的腹腔内注射抑制了异种移植模型中的肿瘤进展。这些发现表明 ATX 在 panNEN 中显著上调，与 panNEN 的进展有关。我们展示了 ATX 作为一种新的生物标志物和治疗靶标的潜力。
