Institute of Molecular Biology and Biophysics, FRC FTM, 630060 Novosibirsk, Russia.
E.N. Meshalkin National Medical Research Center, 630055 Novosibirsk, Russia.
Int J Mol Sci. 2021 Dec 12;22(24):13350. doi: 10.3390/ijms222413350.
Intensive adjuvant radiotherapy (RT) is a standard treatment for glioblastoma multiforme (GBM) patients; however, its effect on the normal brain tissue remains unclear. Here, we investigated the short-term effects of multiple irradiation on the cellular and extracellular glycosylated components of normal brain tissue and their functional significance. Triple irradiation (7 Gy*3 days) of C57Bl/6 mouse brain inhibited the viability, proliferation and biosynthetic activity of normal glial cells, resulting in a fast brain-zone-dependent deregulation of the expression of proteoglycans (PGs) (decorin, biglycan, versican, brevican and CD44). Complex time-point-specific (24-72 h) changes in decorin and brevican protein and chondroitin sulfate (CS) and heparan sulfate (HS) content suggested deterioration of the PGs glycosylation in irradiated brain tissue, while the transcriptional activity of HS-biosynthetic system remained unchanged. The primary glial cultures and organotypic slices from triple-irradiated brain tissue were more susceptible to GBM U87 cells' adhesion and proliferation in co-culture systems in vitro and ex vivo. In summary, multiple irradiation affects glycosylated components of normal brain extracellular matrix (ECM) through inhibition of the functional activity of normal glial cells. The changed content and pattern of PGs and GAGs in irradiated brain tissues are accompanied by the increased adhesion and proliferation of GBM cells, suggesting a novel molecular mechanism of negative side-effects of anti-GBM radiotherapy.
强化辅助放疗（RT）是多形性胶质母细胞瘤（GBM）患者的标准治疗方法；然而，其对正常脑组织的影响尚不清楚。在这里，我们研究了多次照射对正常脑组织细胞和细胞外糖基化成分的短期影响及其功能意义。对 C57Bl/6 小鼠脑进行三次照射（7 Gy*3 天）抑制了正常神经胶质细胞的活力、增殖和生物合成活性，导致脑区依赖性蛋白聚糖（PGs）（decorin、biglycan、versican、brevican 和 CD44）表达快速失调。decorin 和 brevican 蛋白以及软骨素硫酸盐（CS）和硫酸乙酰肝素（HS）含量的复杂时间点特异性（24-72 h）变化表明，照射脑组织中 PGs 的糖基化恶化，而 HS 生物合成系统的转录活性保持不变。来自三次照射脑组织的原代神经胶质培养物和器官型切片在体外和离体共培养系统中对 GBM U87 细胞的粘附和增殖更为敏感。总之，多次照射通过抑制正常神经胶质细胞的功能活性来影响正常脑细胞外基质（ECM）的糖基化成分。照射脑组织中 PGs 和 GAGs 的含量和模式发生变化，伴随着 GBM 细胞的粘附和增殖增加，提示抗 GBM 放疗的负性副作用的新分子机制。
