Jung Karen, Sabri Siham, Hanson John, Xu Yaoxian, Wang Ying Wayne, Lai Raymond, Abdulkarim Bassam S
a Department of Oncology ; University of Alberta ; Edmonton , Canada.
b Department of Oncology ; McGill University ; Montreal , Canada.
Cancer Biol Ther. 2015;16(9):1281-8. doi: 10.1080/15384047.2015.1056945.
Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n = 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p = 0 .032), moist desquamation (p = 0 .027), and CTC grade (p = 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p = 0 .069), moist desquamation (p = 0 .037), and CTC grade (p = 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.
放射治疗（RT）作为早期乳腺癌患者术后的一线治疗方法，至少40%接受治疗的患者会出现急性皮肤毒性。单核细胞衍生的巨噬细胞在损伤部位被特定的全身细胞因子极化为功能不同的（M1或M2）活化表型，已知这些细胞因子在受照射组织的损伤和修复转变中起关键作用。M1和M2巨噬细胞在RT诱导的急性皮肤毒性中的作用尚待确定。我们研究了M1和M2巨噬细胞作为早期乳腺癌患者保乳术后接受辅助RT治疗时RT诱导皮肤毒性预测因素的潜在价值。对参与一项前瞻性临床研究（n = 49）的患者采集的血样在基线时以及首次给予2Gy RT剂量后进行分析。我们设计了一种体外培养系统，将患者血液中的单核细胞分化为巨噬细胞，并在对其“M1/M2”活化标志物、诱导型一氧化氮合酶（iNOS）、精氨酸酶1（Arg1）和转化生长因子β1（TGFß1）进行定量分析之前，用M1或M2诱导细胞因子对其进行处理。使用通用毒性标准（CTC）分级对皮肤反应进行客观评估，进行统计分析以将实验数据与急性皮肤毒性的临床评估相关联。精氨酸酶1（ARG1）mRNA水平升高与更高等级的红斑、湿性脱屑和CTC分级显著相关。多变量分析显示，单次RT剂量后巨噬细胞中ARG1表达增加是红斑（p = 0.032）、湿性脱屑（p = 0.027）和CTC分级（p = 0.056）的独立预后因素。有趣的是，对用白细胞介素-4（IL-4）刺激的巨噬细胞中ARG1 mRNA表达的多变量分析也显示出对预测急性RT诱导毒性因素、红斑（p = 0.069）、湿性脱屑（p = 0.037）和CTC分级（p = 0.046）的独立预后价值。总之，我们的研究结果首次强调了ARG1 mRNA水平升高作为RT诱导急性皮肤毒性的早期独立预测生物标志物的生物学意义。
