Yagi Tomohiko, Kagawa Shunsuke, Nogi Shohei, Taniguchi Atsuki, Yoshimoto Masashi, Suemori Kanto, Nagai Yasuo, Fujita Shuto, Kuroda Shinji, Kikuchi Satoru, Kakiuchi Yoshihiko, Teraishi Fuminori, Takagi Kosei, Ohara Toshiaki, Tazawa Hiroshi, Fujiwara Toshiyoshi
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan.
Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan.
Cancer Immunol Immunother. 2025 Feb 4;74(3):96. doi: 10.1007/s00262-025-03946-z.
The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression.
To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils.
In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells.
CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.
中性粒细胞获得促肿瘤特性的机制仍知之甚少。在胰腺癌中，癌症相关成纤维细胞（CAFs）可能与中性粒细胞相互作用，引导它们促进肿瘤进展。
为验证CAFs与中性粒细胞之间的关联，在临床切除的胰腺癌标本中检测中性粒细胞的定位。通过在癌症条件培养基中培养产生CAFs，并检测这些CAFs对中性粒细胞的影响。体外迁移和侵袭试验评估CAF激活的中性粒细胞对癌细胞的作用。还探索了激活的中性粒细胞分泌的因子。最后，测试吡非尼酮（PFD）以确定它是否能抑制激活的中性粒细胞的促肿瘤功能。
在胰腺癌标本中，中性粒细胞倾向于与IL-6阳性的CAFs共定位。与CAFs共培养的中性粒细胞迁移能力增强，寿命延长。CAF影响的中性粒细胞增强了胰腺癌细胞的迁移和侵袭活性。IL-8是中性粒细胞分泌上调最明显的细胞因子。PFD抑制CAF刺激的中性粒细胞分泌IL-8，并减轻胰腺癌细胞的恶性特征。
CAFs激活中性粒细胞并增强胰腺癌的恶性表型。PFD可破坏癌细胞、CAFs和中性粒细胞之间的相互作用，突出了一种潜在的治疗方法。
