Fernström E, Minta K, Andreasson U, Sandelius Å, Wasling P, Brinkmalm A, Höglund K, Blennow K, Nyman J, Zetterberg H, Kalm M
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
J Intern Med. 2018 Apr 17. doi: 10.1111/joim.12763.
Advances in the treatment of brain tumours have increased the number of long-term survivors, but at the cost of side effects following cranial radiotherapy ranging from neurocognitive deficits to outright tissue necrosis. At present, there are no tools reflecting the molecular mechanisms underlying such side effects, and thus no means to evaluate interventional effects after cranial radiotherapy. Therefore, fluid biomarkers are of great clinical interest.
Cerebrospinal fluid (CSF) levels of proteins involved in inflammatory signalling, synaptic plasticity and extracellular matrix (ECM) integrity were investigated following radiotherapy to the brain.
Patients with small-cell lung cancer (SCLC) eligible for prophylactic cranial irradiation (PCI) were asked to participate in the study. PCI was prescribed either as 2 Gy/fraction to a total dose of 30 Gy (limited disease) or 4 Gy/fraction to 20 Gy (extensive disease). CSF was collected by lumbar puncture at baseline, 3 months and 1 year following PCI. Protein concentrations were measured using immunobased assays or mass spectrometry.
The inflammatory markers IL-15, IL-16 and MCP-1/CCL2 were elevated in CSF 3 months following PCI compared to baseline. The plasticity marker GAP-43 was elevated 3 months following PCI, and the same trend was seen for SNAP-25, but not for SYT1. The investigated ECM proteins, brevican and neurocan, showed a decline following PCI. There was a strong correlation between the progressive decline of soluble APPα and brevican levels.
To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.
脑肿瘤治疗的进展增加了长期存活者的数量，但代价是颅脑放疗后的副作用，范围从神经认知缺陷到直接的组织坏死。目前，尚无反映此类副作用潜在分子机制的工具，因此也没有评估颅脑放疗后干预效果的方法。所以，体液生物标志物具有重大临床意义。
研究脑部放疗后，参与炎症信号传导、突触可塑性和细胞外基质（ECM）完整性的蛋白质在脑脊液（CSF）中的水平。
邀请符合预防性颅脑照射（PCI）条件的小细胞肺癌（SCLC）患者参与研究。PCI方案为：局限性疾病患者给予2 Gy/分次，总剂量30 Gy；广泛性疾病患者给予4 Gy/分次，总剂量20 Gy。在PCI前基线、3个月和1年后通过腰椎穿刺采集脑脊液。使用基于免疫的检测方法或质谱法测量蛋白质浓度。
与基线相比，PCI后3个月脑脊液中炎症标志物白细胞介素-15（IL-15）、白细胞介素-16（IL-16）和单核细胞趋化蛋白-1/CCL2（MCP-1/CCL2）升高。可塑性标志物生长相关蛋白43（GAP-43）在PCI后3个月升高，突触小体相关蛋白25（SNAP-25）也呈现相同趋势，但突触结合蛋白1（SYT1）未出现此趋势。所研究的ECM蛋白，短蛋白聚糖和神经蛋白聚糖，在PCI后呈下降趋势。可溶性淀粉样前体蛋白α（sAPPα）和短蛋白聚糖水平的逐渐下降之间存在强相关性。
据我们所知，这是首次表明癌症患者的ECM相关蛋白受颅脑放疗影响。这些发现可能有助于我们更好地理解放疗后副作用背后的机制。
