Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565‑0871, Japan.
Laboratory of Immunosenescence, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567‑0085, Japan.
Oncol Rep. 2023 May;49(5). doi: 10.3892/or.2023.8535. Epub 2023 Mar 31.
Cancer‑associated fibroblasts (CAFs) are implicated in the strong malignancy of pancreatic cancer (PC). Various CAF subtypes have different functions, and their heterogeneity likely influence the malignancy of PC. Meanwhile, it is known that senescent cells can create a tumor‑promoting microenvironment by inducing a senescence‑associated secretory phenotype (SASP). In the present study, the effects of individual differences in CAFs on PC malignancy were investigated with a focus on cellular senescence. First, primary cultures of CAFs from 8 PC patients were generated and co‑cultured with PC cell lines. This co‑culture assay showed that differences in CAFs induce differences in PC cell proliferation. It was further investigated which clinical factors affected the malignant potential of CAF and it was found that the difference of malignant potential of each CAF was marginally related to the age of original patients. Next, to verify the senescence of CAFs really affected the malignant potential of CAF, PCR array analysis of each CAF sample was performed and it was revealed that expression of genes about cellular senescence and SASP such as tumor protein p53, nuclear factor kappa B subunit 1, and IL6, are related to the malignant potential of CAFs impacting on PC proliferation. Finally, to elucidate the effect of p53‑mediated cellular senescence of CAFs on malignant potential of PC, it was examined whether CAFs with the treatment of p53 inhibitor affected PC cell proliferation in co‑culture assays. The treatment of CAFs with p53 inhibitor significantly suppressed PC cell proliferation. In addition, a comparison of the concentration of IL‑6, a SASP cytokine, in the co‑culture supernatant showed a significant decrease in the sample after p53 inhibitor treatment. In conclusion, the present results suggested that proliferation potential of PC may be related to p53‑mediated cellular senescence and SASP of CAFs.
癌相关成纤维细胞（CAFs）被认为与胰腺癌（PC）的强恶性有关。各种 CAF 亚型具有不同的功能，其异质性可能影响 PC 的恶性程度。同时，已知衰老细胞可以通过诱导衰老相关分泌表型（SASP）来创建促进肿瘤的微环境。在本研究中，重点研究了 CAF 的个体差异对 PC 恶性程度的影响，特别是细胞衰老。首先，从 8 名 PC 患者中生成了原代 CAF 培养物，并与 PC 细胞系共培养。该共培养实验表明，CAF 的差异诱导了 PC 细胞增殖的差异。进一步研究了哪些临床因素影响 CAF 的恶性潜能，发现每个 CAF 的恶性潜能差异与原患者的年龄有一定的关系。接下来，为了验证 CAF 的衰老是否真的影响 CAF 的恶性潜能，对每个 CAF 样本进行了 PCR 阵列分析，结果表明，与 CAF 恶性潜能相关的基因，如肿瘤蛋白 p53、核因子 kappa B 亚单位 1 和 IL6 等，表达细胞衰老和 SASP 的基因。最后，为了阐明 CAF 中 p53 介导的细胞衰老对 PC 恶性潜能的影响，在共培养实验中研究了用 p53 抑制剂处理 CAF 是否影响 PC 细胞的增殖。用 p53 抑制剂处理 CAF 显著抑制了 PC 细胞的增殖。此外，对共培养上清液中 SASP 细胞因子 IL-6 的浓度进行了比较，结果表明，p53 抑制剂处理后的样本中 IL-6 浓度显著降低。综上所述，本研究结果表明，PC 的增殖潜能可能与 CAF 中的 p53 介导的细胞衰老和 SASP 有关。
