Zakaria Rasheed, Platt-Higgins Angela, Rathi Nitika, Crooks Daniel, Brodbelt Andrew, Chavredakis Emmanuel, Lawson David, Jenkinson Michael D, Rudland Philip S
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Br J Cancer. 2016 May 10;114(10):1101-8. doi: 10.1038/bjc.2016.103. Epub 2016 Apr 21.
Understanding the factors that drive recurrence and radiosensitivity in brain metastases would improve prediction of outcomes, treatment planning and development of therapeutics. We investigated the expression of known metastasis-inducing proteins in human brain metastases.
Immunohistochemistry on metastases removed at neurosurgery from 138 patients to determine the degree and pattern of expression of the proteins S100A4, S100P, AGR2, osteopontin (OPN) and the DNA repair marker FANCD2. Validation of significant findings in a separate prospective series with the investigation of intra-tumoral heterogeneity using image-guided sampling. Assessment of S100A4 expression in brain metastatic and non-metastatic primary breast carcinomas.
There was widespread staining for OPN, S100A4, S100P and AGR2 in human brain metastases. Positive staining for S100A4 was independently associated with a shorter time to intracranial progression after resection in multivariate analysis (hazard ratio for negative over positive staining=0.17, 95% CI: 0.04-0.74, P=0.018). S100A4 was expressed at the leading edge of brain metastases in image guided sampling and overexpressed in brain metastatic vs non-brain metastatic primary breast carcinomas. Staining for OPN was associated with a significant increase in survival time after post-operative whole-brain radiotherapy in retrospective (OPN negative 3.43 months, 95% CI: 1.36-5.51 vs OPN positive, 11.20 months 95% CI: 7.68-14.72, Log rank test, P<0.001) and validation populations.
Proteins known to be involved in cellular adhesion and migration in vitro, and metastasis in vivo are significantly expressed in human brain metastases and may be useful biomarkers of intracranial progression and radiosensitivity.
了解驱动脑转移复发和放射敏感性的因素将改善对预后的预测、治疗方案的制定以及治疗方法的开发。我们研究了已知的转移诱导蛋白在人脑转移瘤中的表达情况。
对138例患者神经外科手术切除的转移瘤进行免疫组织化学检测，以确定蛋白S100A4、S100P、AGR2、骨桥蛋白（OPN）和DNA修复标志物FANCD2的表达程度和模式。在一个单独的前瞻性系列中对重要发现进行验证，并使用图像引导采样研究肿瘤内异质性。评估S100A4在脑转移和非转移原发性乳腺癌中的表达。
在人脑转移瘤中，OPN、S100A4、S100P和AGR2存在广泛染色。在多变量分析中，S100A4阳性染色与切除术后颅内进展时间较短独立相关（阴性染色与阳性染色的风险比=0.17，95%CI：0.04-0.74，P=0.018）。在图像引导采样中，S100A4在脑转移瘤的前沿表达，且在脑转移原发性乳腺癌中相对于非脑转移原发性乳腺癌过表达。回顾性研究（OPN阴性3.43个月，95%CI：1.36-5.51；OPN阳性11.20个月，95%CI：7.68-14.72，对数秩检验，P<0.001）和验证人群中，OPN染色与术后全脑放疗后的生存时间显著延长相关。
已知在体外参与细胞黏附和迁移以及在体内参与转移的蛋白在人脑转移瘤中显著表达，可能是颅内进展和放射敏感性的有用生物标志物。
