Women's Cancer's Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Cancer Res. 2012 Jan 1;72(1):144-53. doi: 10.1158/0008-5472.CAN-11-1904.
Brain metastases are a significant cause of morbidity and mortality for patients with cancer, yet preventative and therapeutic options remain an unmet need. The cytokine pigment epithelium-derived factor (PEDF) is downregulated in resected human brain metastases of breast cancer compared with primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here, we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences.
脑转移是癌症患者发病率和死亡率的重要原因，但预防和治疗选择仍然是未满足的需求。细胞因子色素上皮衍生因子（PEDF）在乳腺癌切除的人脑转移瘤中与原发性乳腺癌相比下调，表明恢复其表达可能会限制转移扩散。在这里，我们表明，人 231-BR 或鼠 4T1-BR 乳腺癌细胞的大实验性脑转移的生长被 PEDF 表达所抑制，这得到了体外分析以及直接颅内植入的支持。值得注意的是，PEDF 的抑制作用不仅迅速，而且独立于该因子对血管生成的影响。与 PEDF 对乳腺癌细胞的细胞毒性作用平行，PEDF 还对神经元发挥了保护作用，使大脑免受肿瘤引起的损伤，这表明表达 PEDF 的肿瘤附近死亡神经元的数量相对减少了 3.5 倍。我们的发现确立了 PEDF 作为脑转移中的转移性抑制剂和神经营养因子，突出了其作为限制脑转移及其局部后果的双重作用。
