Centre for Tumor Biology, Barts Cancer Institute-a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London, England.
Gastroenterology. 2011 Oct;141(4):1486-97, 1497.e1-14. doi: 10.1053/j.gastro.2011.06.047. Epub 2011 Jun 24.
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.
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.
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 β-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-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs).
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.
胰腺导管腺癌患者缺乏维生素 A，导致胰腺星状细胞（PSCs）被激活。我们研究了是否将视黄醇恢复到 PSCs 中可以恢复其静止状态并影响相邻的癌细胞。
在二维和三维培养条件下（生理性器官型培养），将 PSCs 和癌细胞系（AsPc1 和 Capan1）暴露于视黄酸（RA）的剂量和异构体中。研究了全反式视黄酸（ATRA）在 LSL-KrasG12D/+；LSL-Trp53R172H/+；Pdx-1-Cre 小鼠（人胰腺导管腺癌模型）中的作用。
在用 ATRA 孵育后，PSCs 处于静止状态，其调节增殖、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的表达发生了改变；无论培养条件或剂量如何。在器官型模型中和在小鼠中，ATRA 诱导 PSCs 静止，从而减少癌细胞增殖和β-连环蛋白向核内易位，增加癌细胞凋亡，并改变肿瘤形态。ATRA 降低了 PSCs 的迁移能力，因此这些细胞在肿瘤和基质的交界处形成了一堵“墙”，阻止了癌细胞的侵袭。将静止的 PSCs 中分泌的卷曲相关蛋白 4（sFRP4）的分泌恢复，可降低癌细胞中的 Wnt-β-连环蛋白信号及其侵袭能力。人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）。
RA 诱导 PSCs 静止并降低其迁移能力，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。
