Meng Guanmin, Wuest Melinda, Tang Xiaoyun, Dufour Jennifer, Zhao YuanYuan, Curtis Jonathan M, McMullen Todd P W, Murray David, Wuest Frank, Brindley David N
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Cancers (Basel). 2019 Nov 19;11(11):1816. doi: 10.3390/cancers11111816.
Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin-lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal "image-guided" RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin-lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT.
乳腺癌患者在肿块切除术后通常会接受多次全乳放射治疗（RT）。我们假设，重复进行放射治疗会逐渐激活自分泌运动因子-溶血磷脂酸-炎症循环。为了验证这一点，使用小动物“图像引导”放射治疗平台，用X射线对正常乳腺脂肪垫和含有小鼠4T1肿瘤的脂肪垫进行照射。单次7.5 Gy的放射剂量以及每日三次7.5 Gy的放射剂量均增加了自分泌运动因子（ATX）的活性，并降低了血浆脂联素浓度。血浆中白细胞介素-6（IL-6）和肿瘤坏死因子α（TNFα）的浓度以及照射后脂肪垫中血管内皮生长因子（VEGF）、粒细胞集落刺激因子（G-CSF）、C-C基序趋化因子11（CCL11）和C-X-C基序趋化因子10（CXCL10）的浓度均升高，但仅在三次放射治疗后出现这种情况。在携带4T1乳腺肿瘤的小鼠中，三次7.5 Gy的放射剂量增强了肿瘤诱导的血浆ATX活性增加，并降低了肿瘤相关乳腺脂肪垫中的脂联素水平。肿瘤相关乳腺脂肪垫和肿瘤中多种炎症介质的表达也增加，同时伴随着CD45+白细胞向肿瘤相关脂肪组织的浸润增加。这项研究提供了新的证据，表明自分泌运动因子产生增加是对放射治疗的早期反应，并且重复进行放射治疗会激活自分泌运动因子-溶血磷脂酸-炎症循环。这种对放射治疗诱导损伤的伤口愈合反应可能会降低后续放射治疗的疗效。
