Begum Asma, McMillan Ross H, Chang Yu-Tai, Penchev Vesselin R, Rajeshkumar N V, Maitra Anirban, Goggins Michael G, Eshelman James R, Wolfgang Christopher L, Rasheed Zeshaan A, Matsui William
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
Departments of Pathology and.
Pancreas. 2019 Mar;48(3):329-334. doi: 10.1097/MPA.0000000000001249.
Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs).
Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor.
Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth.
Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.
癌症相关成纤维细胞（CAFs）通过促进肿瘤细胞迁移和耐药性在胰腺导管腺癌（PDAC）进展中发挥重要作用。我们确定了CAFs对PDAC癌症干细胞（CSCs）的影响。
将患者肿瘤来源的成纤维细胞系与PDAC细胞共培养，并使用集落形成试验检测其克隆生长和自我更新能力，以及体外迁移能力。通过流式细胞术确定CSCs频率的变化。使用针对β1整合素和FAK的短发夹RNA以及小分子FAK抑制剂评估整合素-黏着斑激酶（FAK）信号传导对CAF介导的克隆生长的影响。
癌症相关成纤维细胞增强了PDAC的克隆生长、自我更新和迁移能力，这与CSCs频率增加有关。这些成纤维细胞被PDAC细胞激活，并增加胶原蛋白合成，导致PDAC细胞中FAK激活。敲低PDAC细胞中的β1整合素和FAK或抑制FAK激酶活性可消除CAFs对克隆生长的影响。
因此，CAFs通过产生I型胶原蛋白增强PDAC细胞中的整合素-FAK信号传导，从而增强PDAC的克隆生长、自我更新和CSCs频率。
