Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
School of Medical Sciences, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
Cancer Res. 2020 Jul 1;80(13):2861-2873. doi: 10.1158/0008-5472.CAN-19-3534. Epub 2020 May 11.
Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue ( = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. SIGNIFICANCE: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.
尽管纤维化基质构成了胰腺疾病的一个组成部分，但不同类型的胰腺疾病所编程的成纤维细胞在表型上是否存在差异尚不清楚。在这里，我们表明，从胰腺导管腺癌 (PDAC)、慢性胰腺炎 (CP)、壶腹周围肿瘤和相邻正常 (NA) 组织中分离的成纤维细胞具有不同的 mRNA 和 miRNA 谱。与 NA 成纤维细胞相比，与 PDAC 相关的成纤维细胞通常对一种抗纤维化刺激物 (NPPB) 的敏感性较低，而对 TGFβ1 和 WNT 等激活的阳性调节剂的反应性更高。在所检查的与疾病相关的成纤维细胞中，PDAC 和 CP 衍生的成纤维细胞具有最大的相似性，但 PDAC 相关的成纤维细胞表达更高水平的 tenascin C (TNC)，这归因于 miR-137，一种 TNC 的新型调节因子。TNC 蛋白和转录本水平在 PDAC 组织中高于 CP 组织，与基质激活水平更高相关，并且从耗尽 TNC 的 PDAC 相关成纤维细胞中提取的条件培养基适度增加了 PDAC 细胞的增殖和 PDAC 细胞的迁移，表明基质 TNC 可能对 PDAC 细胞具有抑制作用。最后，与 CP 相比，PDAC 患者的循环 TNC 水平更高。我们对胰腺成纤维细胞编程作为疾病特异性的特征描述对治疗靶向和研究中使用成纤维细胞的方式具有重要意义。意义：从各种类型的胰腺疾病中分离的原代成纤维细胞在培养中具有并保留独特的分子和功能特征，为治疗开发和疾病特异性研究提供了一系列细胞模型。
