期刊
SCIENCE SIGNALING
卷 8, 期 388, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaa5823
关键词
-
资金
- NIH grant [R01 CA169702, K23 CA148964-01, HL42093]
- Viragh Foundation
- Skip Viragh Pancreatic Cancer Center at Johns Hopkins
- Lefkofsky Family Foundation
- National Cancer Institute Specialized Programs of Research Excellence in Gastrointestinal Cancers grant [P50 CA062924]
- Sidney Kimmel Comprehensive Cancer Center grant [P30 CA006973]
- Lustgarten Foundation grant
- [MOD FY15-226]
Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin-plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive andmetastatic potential in culture and inmice. However, restoring Sema3D in AnxA2-null cells did not entirely rescuemetastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively lowSema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据