PDF(Pubmed)
Abstract：
BACKGROUND: Cancer-associated fibroblasts (CAFs) consist of heterogeneous connective tissue cells and are often constituting the most abundant cell type in the tumor stroma. Radiation effects on tumor stromal components like CAFs in the context of radiation treatment is not well-described.
OBJECTIVE: This study explores potential changes induced by ionizing radiation (IR) on platelet-derived growth factor (PDGF)/PDGFRs and transforming growth factor-beta (TGF-β)/TGFβRs signaling systems in CAFs.
RESULTS: Experiments were carried out by employing primary cultures of human CAFs isolated from freshly resected non-small cell lung carcinoma tumor tissues. CAF cultures from nine donors were treated with one high (1 × 18 Gy) or three fractionated (3 × 6 Gy) radiation doses. Alterations in expression levels of TGFβRII and PDGFRα/β induced by IR were analyzed by western blots and flow cytometry. In the presence or absence of cognate ligands, receptor activation was studied in nonirradiated and irradiated CAFs. Radiation exposure did not exert changes in expression of PDGF or TGF-β receptors in CAFs. Additionally, IR alone was unable to trigger activation of either receptor. The radiation regimens tested did not affect PDGFRβ signaling in the presence of PDGF-BB. In contrast, signaling via pSmad2/3 and pSmad1/5/8 appeared to be down-regulated in irradiated CAFs after stimulation with TGF-β, as compared with controls.
CONCLUSIONS: Our data demonstrate that IR by itself is insufficient to induce measurable changes in PDGF or TGF-β receptor expression levels or to induce receptor activation in CAFs. However, in the presence of their respective ligands, exposure to radiation at certain doses appear to interfere with TGF-β receptor signaling.
OBJECTIVE: This study explores potential changes induced by ionizing radiation (IR) on platelet-derived growth factor (PDGF)/PDGFRs and transforming growth factor-beta (TGF-β)/TGFβRs signaling systems in CAFs.
RESULTS: Experiments were carried out by employing primary cultures of human CAFs isolated from freshly resected non-small cell lung carcinoma tumor tissues. CAF cultures from nine donors were treated with one high (1 × 18 Gy) or three fractionated (3 × 6 Gy) radiation doses. Alterations in expression levels of TGFβRII and PDGFRα/β induced by IR were analyzed by western blots and flow cytometry. In the presence or absence of cognate ligands, receptor activation was studied in nonirradiated and irradiated CAFs. Radiation exposure did not exert changes in expression of PDGF or TGF-β receptors in CAFs. Additionally, IR alone was unable to trigger activation of either receptor. The radiation regimens tested did not affect PDGFRβ signaling in the presence of PDGF-BB. In contrast, signaling via pSmad2/3 and pSmad1/5/8 appeared to be down-regulated in irradiated CAFs after stimulation with TGF-β, as compared with controls.
CONCLUSIONS: Our data demonstrate that IR by itself is insufficient to induce measurable changes in PDGF or TGF-β receptor expression levels or to induce receptor activation in CAFs. However, in the presence of their respective ligands, exposure to radiation at certain doses appear to interfere with TGF-β receptor signaling.
摘要：
背景：癌症相关成纤维细胞（CAF）由异质结缔组织细胞组成，通常构成肿瘤基质中最丰富的细胞类型。在放射治疗的背景下，对肿瘤基质成分如CAF的辐射效应没有得到很好的描述。
目的：本研究探讨了电离辐射（IR）对CAFs中血小板衍生生长因子（PDGF）/PDGFR和转化生长因子-β（TGF-β）/TGFβRs信号系统的潜在变化。
结果:通过使用从新鲜切除的非小细胞肺癌肿瘤组织中分离的人CAF的原代培养物进行实验。来自9个供体的CAF培养物用1个高（1×18Gy）或3个分级（3×6Gy）辐射剂量处理。通过蛋白质印迹和流式细胞术分析由IR诱导的TGFβRII和PDGFRα/β表达水平的改变。在存在或不存在同源配体的情况下，在未辐照和辐照的CAFs中研究了受体激活。辐射暴露不会改变CAF中PDGF或TGF-β受体的表达。此外,单独的IR不能触发任一受体的激活。在存在PDGF-BB的情况下,测试的放射方案不影响PDGFRβ信号传导。相比之下,在TGF-β刺激后，通过pSmad2/3和pSmad1/5/8的信号在辐照的CAF中似乎下调，与对照组相比。
结论：我们的数据表明，IR本身不足以诱导PDGF或TGF-β受体表达水平的可测量变化或诱导CAF中的受体激活。然而,在它们各自的配体存在下，暴露于某些剂量的辐射似乎干扰TGF-β受体信号。
目的：本研究探讨了电离辐射（IR）对CAFs中血小板衍生生长因子（PDGF）/PDGFR和转化生长因子-β（TGF-β）/TGFβRs信号系统的潜在变化。
结果:通过使用从新鲜切除的非小细胞肺癌肿瘤组织中分离的人CAF的原代培养物进行实验。来自9个供体的CAF培养物用1个高（1×18Gy）或3个分级（3×6Gy）辐射剂量处理。通过蛋白质印迹和流式细胞术分析由IR诱导的TGFβRII和PDGFRα/β表达水平的改变。在存在或不存在同源配体的情况下，在未辐照和辐照的CAFs中研究了受体激活。辐射暴露不会改变CAF中PDGF或TGF-β受体的表达。此外,单独的IR不能触发任一受体的激活。在存在PDGF-BB的情况下,测试的放射方案不影响PDGFRβ信号传导。相比之下,在TGF-β刺激后，通过pSmad2/3和pSmad1/5/8的信号在辐照的CAF中似乎下调，与对照组相比。
结论：我们的数据表明，IR本身不足以诱导PDGF或TGF-β受体表达水平的可测量变化或诱导CAF中的受体激活。然而,在它们各自的配体存在下，暴露于某些剂量的辐射似乎干扰TGF-β受体信号。
