Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
Department of Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan.
Br J Cancer. 2022 Mar;126(4):628-639. doi: 10.1038/s41416-021-01639-9. Epub 2021 Nov 25.
The treatment of pancreatic cancer (PDAC) remains clinically challenging, and neoadjuvant therapy (NAT) offers down staging and improved surgical resectability. Abundant fibrous stroma is involved in malignant characteristic of PDAC. We aimed to investigate tissue remodelling, particularly the alteration of the collagen architecture of the PDAC microenvironment by NAT.
We analysed the alteration of collagen and gene expression profiles in PDAC tissues after NAT. Additionally, we examined the biological role of Ephrin-A5 using primary cultured cancer-associated fibroblasts (CAFs).
The expression of type I, III, IV, and V collagen was reduced in PDAC tissues after effective NAT. The bioinformatics approach provided comprehensive insights into NAT-induced matrix remodelling, which showed Ephrin-A signalling as a likely pathway and Ephrin-A5 (encoded by EFNA5) as a crucial ligand. Effective NAT reduced the number of Ephrin-A5 cells, which were mainly CAFs; this inversely correlated with the clinical tumour shrinkage rate. Experimental exposure to radiation and chemotherapeutic agents suppressed proliferation, EFNA5 expression, and collagen synthesis in CAFs. Forced EFNA5 expression altered CAF collagen gene profiles similar to those found in PDAC tissues after NAT.
These results suggest that effective NAT changes the extracellular matrix with collagen profiles through CAFs and their Ephrin-A5 expression.
胰腺癌（PDAC）的治疗仍然具有临床挑战性，新辅助治疗（NAT）可使肿瘤降级并提高手术可切除性。丰富的纤维基质参与了 PDAC 的恶性特征。我们旨在研究组织重塑，特别是 NAT 对 PDAC 微环境胶原结构的改变。
我们分析了 NAT 后 PDAC 组织中胶原和基因表达谱的改变。此外，我们还使用原代培养的癌相关成纤维细胞（CAFs）研究了 Ephrin-A5 的生物学作用。
有效的 NAT 后，PDAC 组织中 I 型、III 型、IV 型和 V 型胶原的表达减少。生物信息学方法全面深入地研究了 NAT 诱导的基质重塑，结果表明 Ephrin-A 信号通路可能是一个关键途径，Ephrin-A5（由 EFNA5 编码）是一个关键配体。有效的 NAT 减少了 Ephrin-A5 细胞（主要是 CAFs）的数量，这与临床肿瘤退缩率呈负相关。实验暴露于辐射和化疗药物会抑制 CAFs 的增殖、EFNA5 表达和胶原合成。强制表达 Ephrin-A5 会改变 CAF 胶原基因谱，类似于 NAT 后 PDAC 组织中的变化。
这些结果表明，有效的 NAT 通过 CAFs 及其 Ephrin-A5 表达改变细胞外基质的胶原谱。
