Retinoic Acid-Induced Pancreatic Stellate Cell Quiescence Reduces Paracrine Wnt-β-Catenin Signaling to Slow Tumor Progression
Retinoic Acid-Induced Pancreatic Stellate Cell Quiescence Reduces Paracrine Wnt-β-Catenin Signaling to Slow Tumor Progression
复制标题
DOI：
10.1053/j.gastro.2011.06.047
复制
发表时间：
2011-10-01
期刊：
影响因子：
29.4
通讯作者：
Kocher, Hemant M.
中科院分区：
文献类型：
--
作者：
Froeling, Fieke E. M.;Feig, Christine;Kocher, Hemant M.
背景与目的：胰腺导管腺癌患者缺乏维生素A，导致胰腺星状细胞（PSCs）活化。我们研究了向PSCs补充视黄醇是否能使其恢复静止状态并影响邻近的癌细胞。
方法：在二维和三维培养条件（生理模拟器官型培养）下，使PSCs和癌细胞系（AsPc1和Capan1）暴露于不同剂量和异构体的视黄酸（RA）中。在LSL - KrasG12D/+；LSL - Trp53R172H/+；Pdx - 1 - Cre小鼠（一种人类胰腺导管腺癌模型）中研究全反式视黄酸（ATRA）的作用。
结果：与ATRA孵育后，无论培养条件或剂量如何，PSCs均处于静止状态，并且调节增殖、形态和运动的基因、编码细胞骨架蛋白和细胞因子的基因以及控制其他功能的基因表达发生改变。在器官型模型和小鼠中，ATRA诱导PSCs静止，从而减少癌细胞增殖以及β - 连环蛋白向细胞核的转位，增加癌细胞凋亡，并改变肿瘤形态。ATRA降低了PSCs的运动性，因此这些细胞在肿瘤与基质之间的连接处形成一道“屏障”，阻止癌细胞侵袭。恢复静止PSCs分泌分泌型卷曲相关蛋白4（sFRP4）可降低癌细胞中的Wnt - β - 连环蛋白信号传导及其侵袭能力。人类原发性和转移性胰腺肿瘤组织中癌细胞核β - 连环蛋白染色强烈，但sFRP4水平较低（在癌细胞和PSCs中）。
结论：RA诱导PSCs静止并降低其运动性，导致周围胰腺癌细胞增殖减少和凋亡增加。RA异构体可能被开发为胰腺癌的治疗试剂。
BACKGROUND & AIMS: Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. METHODS: PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma. RESULTS: After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of beta-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-beta-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear beta-catenin but had low levels of sFRP4 (in cancer cells and PSCs). CONCLUSIONS: RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer.