Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
Department of Radiation Oncology, Radboud University Medical Center, Nijmegen.
Radiother Oncol. 2013 Sep;108(3):440-445. doi: 10.1016/j.radonc.2013.06.020. Epub 2013 Jul 25.
Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance.
NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry.
Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype.
We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy.
晚期 NSCLC 患者的生存率<15%。NOTCH 通路在肺发育和生理过程中发挥着重要作用，但在肺癌中常常失调，使其成为潜在的治疗靶点。我们研究了 NSCLC 中的 NOTCH 信号，并假设高 NOTCH 活性有助于辐射抵抗。
采用定量 RT-PCR 检测 NSCLC 患者样本中的 NOTCH 信号。生成具有高或阻断 NOTCH 活性的 H460 NSCLC 细胞，并通过集落形成试验监测其辐射敏感性。在体内，通过生长延迟评估异种移植瘤的辐射反应。通过免疫组织化学分析微环境参数。
肿瘤中 NOTCH 活性高的患者无病生存期明显更差。体外，NOTCH 活性不影响 NSCLC 细胞的增殖或内在放射敏感性。相比之下，阻断 NOTCH 活性的异种移植瘤生长速度比野生型肿瘤慢。高 NOTCH 活性的肿瘤生长速度明显更快，缺氧程度更高，并表现出辐射抵抗表型。
我们证明了 NOTCH 在肿瘤生长中的重要作用，并将高 NOTCH 活性与不良预后和辐射抵抗相关联。阻断 NSCLC 中的 NOTCH 活性可能是改善放疗后结局的有前途的干预措施。
