Department of Chemistry, Washington University, St Louis, Missouri.
Department of Radiology, Washington University, St Louis, Missouri; Department of Radiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Int J Radiat Oncol Biol Phys. 2019 Jan 1;103(1):190-194. doi: 10.1016/j.ijrobp.2018.08.033. Epub 2018 Aug 30.
Glioblastoma (GBM) remains incurable, despite state-of-the-art treatment involving surgical resection, chemotherapy, and radiation. GBM invariably recurs as a highly invasive and aggressive phenotype, with the majority of recurrences within the radiation therapy treatment field. Although a large body of literature reporting on primary GBM exists, comprehensive studies of how prior irradiation alters recurrent tumor growth are lacking. An animal model that replicates the delayed effects of radiation therapy on the brain microenvironment, and its impact on the development of recurrent GBM, would be a significant advance.
Cohorts of mice received a single fraction of 0, 20, 30, or 40 Gy Gamma Knife irradiation. Naïve, nonirradiated mouse GBM tumor cells were implanted into the ipsilateral hemisphere 6 weeks postirradiation. Tumor growth was measured by magnetic resonance imaging, and animal survival was assessed by monitoring weight loss. Magnetic resonance imaging results were supported by hemotoxylin and eosin histology.
Tumorous lesions generated from orthotopic implantation of nonirradiated mouse GBM tumor cells into irradiated mouse brain grew far more aggressively and invasively than implantation of these same cells into nonirradiated brain. Lesions in irradiated brain tissue were significantly larger, more necrotic, and more vascular than those in control animals with increased invasiveness of tumor cells in the periphery, consistent with the histologic features commonly observed in recurrent high-grade tumors in patients.
Irradiation of normal brain primes the targeted cellular microenvironment for aggressive tumor growth when naïve (not previously irradiated) cancer cells are subsequently introduced. The resultant growth pattern is similar to the highly aggressive pattern of tumor regrowth observed clinically after therapeutic radiation therapy. The mouse model offers an avenue for determining the cellular and molecular basis for the aggressiveness of recurrent GBM.
尽管采用了包括手术切除、化疗和放疗在内的最先进的治疗方法，胶质母细胞瘤（GBM）仍然无法治愈。GBM 总是以高度侵袭性和侵袭性的表型复发，大多数复发发生在放射治疗治疗区域内。尽管有大量文献报道原发性 GBM，但缺乏关于先前照射如何改变复发性肿瘤生长的综合研究。如果有一种动物模型能够复制放射治疗对大脑微环境的延迟效应及其对复发性 GBM 发展的影响，那将是一项重大进展。
两组小鼠分别接受单次 0、20、30 或 40Gy 伽玛刀照射。照射后 6 周，将未照射的、非照射的小鼠 GBM 肿瘤细胞植入同侧半球。通过磁共振成像测量肿瘤生长，通过监测体重减轻评估动物存活。磁共振成像结果得到苏木精和伊红组织学的支持。
将未经照射的小鼠 GBM 肿瘤细胞原位植入照射后的小鼠大脑中产生的肿瘤病变比将这些相同的细胞植入未照射的大脑中生长得更具侵袭性和侵袭性。照射脑组织中的病变明显大于、更坏死和更血管化，与患者中常见的复发性高级别肿瘤的组织学特征一致，肿瘤细胞在周围的侵袭性增加。
正常大脑的照射为随后引入的幼稚（未先前照射）癌细胞的侵袭性肿瘤生长启动了靶向细胞微环境。由此产生的生长模式类似于治疗性放射治疗后临床上观察到的高度侵袭性肿瘤再生长模式。该小鼠模型为确定复发性 GBM 侵袭性的细胞和分子基础提供了一个途径。
