Department of Anatomy and Experimental Morphology and Core Facility Small Animal Irradiation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department for Radiation Oncology, Ambulatory Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Anatomy and Experimental Morphology and Core Facility Small Animal Irradiation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Int J Radiat Oncol Biol Phys. 2018 Mar 15;100(4):1044-1056. doi: 10.1016/j.ijrobp.2017.11.044. Epub 2017 Dec 6.
To investigated the influence of radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT), or chemotherapy (ChT) on small cell lung cancer metastases in 2 xenograft models.
A total of 1 × 10 human small cell lung cancer cells (OH1, H69) were subcutaneously injected into severe combined immunodeficiency mice to form a local primary tumor node at the lower trunk. Radiation therapy, OP, RChT, or ChT were started after development of palpable tumors. Chemotherapy was given as a single intraperitoneal injection of cisplatin. Radiation therapy was 5 × 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control group A) and at the end of the experiment (control group B). Proapoptotic, antiproliferative, antiangiogenic, and hypoxic effects were assessed by Feulgen, Ki67, S1P1 receptor, and hypoxia-inducible factor 1α staining, respectively. Quantitative Alu-polymerase chain reaction was used to determine circulating tumor cells in the blood, and disseminated tumor cells in the lungs, bone marrow, liver, and brain.
In both xenograft models, RT and RChT abrogated local tumor growth, indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in the case of relapse-free surgery could similar effects be achieved by OP.
Our models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regard to suppression of circulating tumor cells and disseminated tumor cells.
在 2 种异种移植模型中研究放射治疗 (RT)、手术 (OP)、放化疗 (RChT) 或化疗 (ChT) 对小细胞肺癌转移的影响。
将 1×10 个人类小细胞肺癌细胞 (OH1、H69) 皮下注射到严重联合免疫缺陷小鼠中，在下躯干形成局部原发性肿瘤结节。在可触及肿瘤形成后开始进行 RT、OP、RChT 或 ChT。化疗采用顺铂单次腹腔内注射。RT 给予局部肿瘤结节 5×10Gy。还实施了另外 2 组来评估未经治疗的小鼠在开始时 (对照组 A) 和实验结束时 (对照组 B) 的原发性肿瘤和远处转移。通过 Feulgen、Ki67、S1P1 受体和缺氧诱导因子 1α 染色分别评估促凋亡、抗增殖、抗血管生成和缺氧作用。定量 Alu-聚合酶链反应用于检测血液中的循环肿瘤细胞和肺部、骨髓、肝脏和大脑中的播散性肿瘤细胞。
在这 2 种异种移植模型中，RT 和 RChT 均能抑制局部肿瘤生长，表现为凋亡增加、细胞增殖减少和微血管密度降低（同等影响所有直径的血管）。对于转移，RT 和 RChT 不仅能拮抗随时间推移的播散增加，而且能减少治疗诱导时血液、肺部和肝脏中已存在的转移负荷。只有在无复发生存手术的情况下，OP 才能获得类似的效果。
我们的模型提供了证据，表明 RT 和 RChT 能根除原发性肿瘤并抑制转移随时间的发展。在局部复发时，与 OP 相比，RT 对抑制循环肿瘤细胞和播散性肿瘤细胞具有有益的效果。
