Department of Radiology, University Hospital of Northern-Norway, Tromsø, Norway.
Molecular &Clinical Inflammation Research Group, Department of Clinical Medicine, University of Tromsø, Norway.
Sci Rep. 2017 Apr 25;7:46714. doi: 10.1038/srep46714.
Cancer-associated fibroblasts (CAFs) are abundantly present in solid tumors and affect tumorigenesis and therapeutic responses. In the context of clinical radiotherapy, the impact of irradiated CAFs to treatment outcomes is largely unexplored. Aiming at improving radiotherapy efficacy, we have here explored the effect of radiation on the inherent pro-tumorigenic capacity of CAFs in animals. Ionizing radiation was delivered to cultured CAFs as single-high or fractionated doses. Tumor development was compared in mice receiving A549 lung tumor cells admixed with irradiated or control CAFs. Biological mechanisms behind tumor growth regulation were investigated by quantitative histology and immunohistochemistry. Viability assessments confirmed that irradiated CAFs are fully functional prior to implantation. However, the enhanced tumorigenic effect observed in tumors co-implanted with control CAFs was abrogated in tumors established with irradiated CAFs. Experiments to ascertain fate of implanted fibroblasts showed that exogenously administered CAFs reside at the implantation site for few days, suggesting that tumor growth regulation from admixed CAFs take place during initial tumor formation. Our work demonstrate that irradiated CAFs lose their pro-tumorigenic potential in vivo, affecting angiogenesis and tumor engraftment. This finding propose a previously unknown advantageous effect induced by radiotherapy, adding to the direct cytotoxic effects on transformed epithelial cells.
癌症相关成纤维细胞 (CAFs) 在实体瘤中大量存在，影响肿瘤发生和治疗反应。在临床放射治疗的背景下，辐照 CAFs 对治疗结果的影响在很大程度上尚未被探索。为了提高放射治疗的疗效，我们在这里研究了辐射对动物 CAFs 固有促肿瘤能力的影响。对培养的 CAFs 进行单次高剂量或分次剂量的电离辐射。将 A549 肺癌细胞与辐照或对照 CAFs 混合后，在小鼠中比较肿瘤的发展。通过定量组织学和免疫组织化学研究肿瘤生长调节的生物学机制。活力评估证实，植入前辐照 CAFs 具有完全的功能。然而，与对照 CAFs 共植入时观察到的增强的致瘤效应在与辐照 CAFs 共植入的肿瘤中被消除。确定植入成纤维细胞命运的实验表明，外源性给予的 CAFs 在植入部位存在几天，这表明混合 CAFs 对肿瘤形成过程中的初始肿瘤生长的调节发生在植入后几天内。我们的工作表明，辐照 CAFs 在体内失去其促肿瘤潜能，影响血管生成和肿瘤植入。这一发现提出了放射治疗诱导的一种以前未知的有利影响，除了对转化上皮细胞的直接细胞毒性作用之外。
