Abstract
Treatment of pancreatic cancer remains clinically challenging and requires the novel therapeutic interventions to improve patient outcome. Neoadjuvant therapy i.e. preoperative treatments comprising chemotherapeutic agents with/without radiation offers down-staging and improvement of surgical resectability. Here, we report that neoadjuvant therapy alters collagen architecture of pancreatic cancer. Transcriptomic profiles of type 1 to type 28 collagens depicted changes of collagen composition due to neoadjuvant therapy. Immunohistochemically, the expressed area of collagen type 1, 3, 4, and 5 were significantly reduced post treatment. The bioinformatic approaches provided a comprehensive insight into treatment-induced matrix remodeling, which showed that Ephrin-A signaling and Ephrin-A5 appeared as a highly possible pathway and a crucial ligand. Ephrin-A5 co-localized with alpha-SMA(+) cancer-associated fibroblasts, whereby Ephrin-A5 have been implicated to synthesize collagens. The Ephrin-A5 positive cells significantly reduced after neoadjuvant therapy, also inversely correlated with tumor shrinkage rate. Using primary culture cells of cancer-associated fibroblasts, experimental exposure of radiation and chemotherapeutic agents suppressed the proliferation of cancer-associated fibroblasts, collagen synthesis and Ephrin-A5 expression. Thus, our studies demonstrate that neoadjuvant therapy down-regulates Ephrin-A5 expression, leading to a change of extracellular matrix structure. It should be a clinical concern of surgical handling when following resection.
Note: This abstract was not presented at the meeting.
Citation Format: Kosei Nakajima, Yoshinori Ino, Sotoshi Nara, Toshimitsu Iwasaki, Nobuyoshi Hiraoka. Neoadjuvant therapy alters collagen architecture of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1229.
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