Department of Women's and Children's Health, Karolinska Institutet, Stockholm, S-17176, Sweden.
Carcinogenesis. 2013 May;34(5):1081-8. doi: 10.1093/carcin/bgt009. Epub 2013 Jan 24.
Tumor-associated inflammation is a driving force in several adult cancers and intake of low-dose aspirin has proven to reduce cancer incidence. Little is known about tumor-associated inflammation in pediatric neoplasms and no in vivo data exists on the effectiveness of low-dose aspirin on established tumors. The present study employs the transgenic TH-MYCN mouse model for neuroblastoma (NB) to evaluate inflammatory patterns paralleling tumor growth in vivo and low-dose aspirin as a therapeutic option for high-risk NB. Spontaneously arising abdominal tumors were monitored for tumor-associated inflammation ex vivo at various stages of disease and homozygous mice received daily low-dose aspirin (10mg/kg) using oral gavage or no treatment, from 4.5 to 6 weeks of age. Using flow cytometry, a transition from an adaptive immune response predominated by CD8(+) T cell in early neoplastic lesions, towards enrichment in immature cells of the innate immune system, including myeloid-derived suppressor cells, dendritic cells and tumor-associated macrophages, was detected during tumor progression. An M1 to M2 transition of tumor-associated macrophages was demonstrated, paralleled by a deterioration of dendritic cell status. Treatment with low-dose aspirin to mice homozygous for the TH-MYCN transgene significantly reduced the tumor burden (P < 0.01), the presence of tumor-associated cells of the innate immune system (P < 0.01), as well as the intratumoral expression of transforming growth factor-β, thromboxane A2 (P < 0.05) and prostaglandin D2 (P < 0.01). In conclusion, tumor-associated inflammation appears as a potential therapeutic target in NB and low-dose aspirin reduces tumor burden in the TH-MYCN transgenic mouse model of NB, hence warranting further studies on aspirin in high-risk NB.
肿瘤相关炎症是几种成人癌症的驱动因素，低剂量阿司匹林的摄入已被证明可降低癌症发病率。小儿肿瘤的肿瘤相关炎症知之甚少，也没有关于低剂量阿司匹林对已建立的肿瘤的有效性的体内数据。本研究采用神经母细胞瘤（NB）的转基因 TH-MYCN 小鼠模型，评估体内肿瘤生长过程中的炎症模式，并评估低剂量阿司匹林作为高危 NB 的治疗选择。在疾病的各个阶段，对自发出现的腹部肿瘤进行离体监测，以评估肿瘤相关炎症，并对纯合子小鼠从 4.5 至 6 周龄起，每日通过口服灌胃给予低剂量阿司匹林（10mg/kg）或不进行治疗。通过流式细胞术检测到，在肿瘤进展过程中，从早期肿瘤病变中以 CD8(+)T 细胞为主的适应性免疫反应向先天免疫系统中未成熟细胞（包括髓系来源的抑制细胞、树突状细胞和肿瘤相关巨噬细胞）的富集转变。证明肿瘤相关巨噬细胞发生 M1 向 M2 的转变，同时树突状细胞状态恶化。对 TH-MYCN 转基因纯合子小鼠进行低剂量阿司匹林治疗可显著降低肿瘤负担（P < 0.01），降低先天免疫系统肿瘤相关细胞的存在（P < 0.01），以及降低肿瘤内转化生长因子-β、血栓素 A2（P < 0.05）和前列腺素 D2（P < 0.01）的表达。总之，肿瘤相关炎症似乎是 NB 的一个潜在治疗靶点，低剂量阿司匹林可降低 TH-MYCN 转基因 NB 小鼠模型中的肿瘤负担，因此有必要进一步研究阿司匹林在高危 NB 中的作用。
