Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan.
Ann Surg Oncol. 2018 Jul;25(7):1868-1879. doi: 10.1245/s10434-018-6431-8. Epub 2018 Apr 19.
The cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) are well known to play a dominant role in distant metastasis. Nevertheless, the effect on CAFs with current chemoradiation therapies remains uncertain.
This study aimed to reveal the role of CAFs under current chemoradiation therapy (CRT) and investigate the factors regulating CAFs.
α-SMA-positive cells in 86 resected PDAC specimens with/without preoperative CRT were evaluated by immunohistochemistry. Various factors, including the plasma levels of vitamin D, were investigated for association with the number of CAFs or distant metastasis-free survival (DMFS). Human pancreatic satellite cells (hPSCs) extracted from clinical specimens were used to validate the factors.
All PDAC samples contained CAFs but the number varied widely. Multivariate analysis for DMFS indicated a larger number of CAFs was a significant risk factor. Univariate analysis for the number of CAFs identified two clinical factors: preoperative CRT and lower plasma levels of vitamin D. In subgroup analysis, the higher plasma level of vitamin D was a dominant factor for longer DMFS in PDAC patients after preoperative CRT. These results were validated by using extracted hPSCs. Irradiation activated stromal cells into CAFs facilitating malignant characteristics of PDAC and the change was inhibited by vitamin D supplementation in vitro.
In conjunction with established current therapies, vitamin D supplementation may be an effective treatment for PDAC patients by inactivating CAFs.
胰腺癌（PDAC）中的癌症相关成纤维细胞（CAFs）在远处转移中起着主导作用，这是众所周知的。然而，目前的放化疗对 CAFs 的影响仍不确定。
本研究旨在揭示 CAFs 在当前放化疗（CRT）下的作用，并研究调节 CAFs 的因素。
通过免疫组织化学法评估 86 例接受/未接受术前 CRT 的 PDAC 标本中α-SMA 阳性细胞。研究了包括维生素 D 血浆水平在内的各种因素与 CAFs 数量或无远处转移生存（DMFS）的相关性。从临床标本中提取的人胰腺卫星细胞（hPSC）用于验证这些因素。
所有 PDAC 标本均含有 CAFs，但数量差异很大。DMFS 的多变量分析表明，CAFs 数量较多是一个显著的危险因素。CAFs 数量的单因素分析确定了两个临床因素：术前 CRT 和维生素 D 血浆水平较低。亚组分析表明，术前 CRT 后 PDAC 患者维生素 D 血浆水平较高是 DMFS 延长的主要因素。这些结果通过提取的 hPSC 得到了验证。体外辐照激活了基质细胞成为 CAFs，促进了 PDAC 的恶性特征，而维生素 D 补充抑制了这种变化。
结合现有的治疗方法，维生素 D 补充可能通过使 CAFs 失活成为 PDAC 患者的有效治疗方法。
