Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer.
Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer.
复制标题
DOI：
10.1111/cas.14689
复制
发表时间：
2021-03
期刊：
影响因子：
5.7
通讯作者：
Kataoka H
中科院分区：
文献类型：
--
作者：
Jinno N;Yoshida M;Hayashi K;Naitoh I;Hori Y;Natsume M;Kato A;Kachi K;Asano G;Atsuta N;Sahashi H;Kataoka H
胰腺导管腺癌（PDAC）患者的腹膜播散和恶性腹水是一个主要的临床问题。溶血磷脂酸（LPA）是一种调节各种癌症进展的脂质介质。基于越来越多的证据表明LPA在恶性腹水中是丰富的，我们将重点放在自分泌运动因子（ATX）上，这是一种分泌的酶，对LPA的产生非常重要。本研究旨在阐明ATX-LPA轴在PDAC恶性腹水中的重要性，并确定ATX是否可作为治疗腹膜播散的分子靶点。在PDAC腹膜播散小鼠模型中，腹水中ATX的量显著高于血清中。使用两种PDAC细胞系AsPC-1和PANC-1的体外研究表明，ATX-LPA信号通过激活下游信号促进癌细胞迁移，并且这种增加的细胞迁移被ATX抑制剂PF-8380抑制。一项体内研究表明，PF-8380可抑制腹膜播散并减少恶性腹水，这些结果已通过生物学分析和体外研究得到验证。此外，腹水中ATX的量与扩散性癌症进展的程度之间存在正相关性。这些结果表明，ATX在腹水中作为腹膜传播的促进剂，并且ATX的靶向必须代表PDAC腹膜传播的有用的和新颖的治疗。我们可以检测到PF-8380对胰腺导管腺癌（PDAC）腹膜内播散的强烈抑制作用，因为生物发光成像和白色-光成像可清楚地观察到这一点。
Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX‐LPA axis in malignant ascites in PDAC and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC‐1 and PANC‐1, showed that ATX‐LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF‐8380. An in vivo study showed that PF‐8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC. We could detect the strong inhibitory effect of PF‐8380 on intraperitoneal dissemination of pancreatic ductal adenocarcinoma (PDAC) as it was clearly visualized by bioluminescence imaging and under white‐light imaging.
登录
查看更多内容
影响因子：
5.7
作者：
Kim S;Kim B;Song YS
通讯作者：
Song YS
影响因子：
5.2
作者：
Benesch MGK;MacIntyre ITK;McMullen TPW;Brindley DN
通讯作者：
Brindley DN
影响因子：
3.9
作者：
Ninou I;Magkrioti C;Aidinis V
通讯作者：
Aidinis V
影响因子：
3.9
作者：
Benesch, Matthew G. K.;Ko, Yi M.;McMullen, Todd P. W.
通讯作者：
McMullen, Todd P. W.
影响因子：
4.8
作者：
Ferry, G;Tellier, E;Saulnier-Blache, JS
通讯作者：
Saulnier-Blache, JS