Crowther Andrew J, Ocasio Jennifer K, Fang Fang, Meidinger Jessica, Wu Jaclyn, Deal Allison M, Chang Sha X, Yuan Hong, Schmid Ralf, Davis Ian, Gershon Timothy R
UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
Cancer Res. 2016 Jun 1;76(11):3211-23. doi: 10.1158/0008-5472.CAN-15-0025. Epub 2016 Apr 13.
While treatments that induce DNA damage are commonly used as anticancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiotherapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine whether the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that Trp53 (p53) was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies, because they retain apoptosis competence. Cancer Res; 76(11); 3211-23. ©2016 AACR.
虽然诱导DNA损伤的治疗方法通常用作抗癌疗法，但DNA损伤产生治疗反应的机制尚未完全明确。在此，我们测试了髓母细胞瘤是否必须具备凋亡能力才能对放疗敏感。放疗敏感性是否需要凋亡一直存在争议。髓母细胞瘤是儿童最常见的恶性脑肿瘤，是一组生物学上异质性的肿瘤，通常对放疗和化疗敏感；80%的髓母细胞瘤患者治疗后能长期存活。我们使用功能遗传学研究来确定在原发性、Shh驱动的髓母细胞瘤小鼠中，辐射产生治疗反应是否需要内源性凋亡途径。我们发现颅脑放疗延长了携带髓母细胞瘤小鼠的生存期并诱导了广泛凋亡。表达分析和条件性缺失研究表明，Trp53（p53）是辐射激活的主要转录调节因子，是治疗反应所必需的。缺失Bax可阻断p53下游的凋亡，足以使肿瘤产生放疗抗性。在无凋亡能力、缺失Bax的肿瘤中，辐射激活了p53依赖性转录，但未引发细胞死亡，并导致出现两个不同的细胞群。大多数接受辐射的肿瘤细胞发生终末分化。然而，血管周围细胞尽管p53被激活，却迅速恢复增殖，表现为干细胞，并迅速导致复发。这些数据表明，辐射必须诱导肿瘤干细胞凋亡才能有效。使内源性凋亡途径失活的突变足以赋予放疗抗性。我们认为髓母细胞瘤通常对DNA损伤疗法敏感，因为它们保留了凋亡能力。《癌症研究》；76(11)；3211 - 23。©2016美国癌症研究协会。
