Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, University College London, London, United Kingdom.
Department of Life Sciences, Institute of Environment and Health, Brunel University London, Uxbridge, United Kingdom. Department of Biomedical Sciences, National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy.
Clin Cancer Res. 2016 Jul 1;22(13):3398-409. doi: 10.1158/1078-0432.CCR-15-2081. Epub 2016 Apr 13.
Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations.
Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann-Whitney tests, respectively. Gene expression was assessed using chip microarrays.
PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas.
Our work reveals a novel PML-I-TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398-409. ©2016 AACR.
神经母细胞瘤是一种起源于交感神经系统的儿童恶性肿瘤，具有复杂的生物学特性，容易转移和复发。高风险、转移性病例部分归因于癌基因（如 MYCN 和 ALK）的扩增或突变，以及染色体 1p 带肿瘤抑制基因的缺失。然而，确定其他途径对于大部分无明显分子改变的神经母细胞瘤是至关重要的。
使用神经母细胞瘤细胞系评估体内和体外的肿瘤生长情况。使用免疫荧光和免疫组化评估组织和细胞中的蛋白表达。使用对数秩和 Mann-Whitney 检验分别计算早幼粒细胞白血病（PML）表达与神经母细胞瘤结局和复发的相关性。使用芯片微阵列评估基因表达。
PML 在发育中的和成人的交感神经系统中被检测到，而在转移性神经母细胞瘤肿瘤中不表达或低表达。低风险癌症（即局部和 MYCN 原癌基因阴性）患者中 PML 表达降低与肿瘤复发强烈相关。PML-I 而不是 PML-IV 亚型通过上调血管生成的关键抑制剂血栓素-2（TSP2）抑制血管生成。最后，PML-I 和 TSP2 的表达与局部神经母细胞瘤中的肿瘤血管生成和复发呈负相关。
我们的工作揭示了一个新的 PML-I-TSP2 轴，用于调节血管生成和癌症复发，这可能用于识别可能受益于化疗的低风险、局限性肿瘤患者。临床癌症研究；22(13)；3398-409。©2016AACR。
