Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.
Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.
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DOI：
10.1158/0008-5472.can-12-2681
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发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
Lahti JM
中科院分区：
文献类型：
--
作者：
Teitz T;Inoue M;Valentine MB;Zhu K;Rehg JE;Zhao W;Finkelstein D;Wang YD;Johnson MD;Calabrese C;Rubinstein M;Hakem R;Weiss WA;Lahti JM
神经母细胞瘤是最常见的儿童颅外实体瘤，占所有儿童癌症死亡的 15%。患者在诊断时经常出现转移性疾病，尤其是骨髓 (BM) 转移性疾病。治疗进展和对转移过程的理解受到限制，部分原因是缺乏携带 BM 疾病的动物模型。广泛使用的转基因模型 Th-MYCN 小鼠在该位点表现出有限的转移。在这里，我们建立了第一个具有遗传免疫活性的小鼠模型，用于治疗转移性神经母细胞瘤，并在骨髓中继发性肿瘤增强。该模型概括了转移性神经母细胞瘤中两种常见的改变，即 MYCN 的过度表达和 caspase-8 表达的丧失。通过将 Th-Cre 转基因小鼠与 caspase-8 条件性敲除小鼠杂交，小鼠 caspase-8 基因在神经嵴谱系细胞中被删除。然后将该小鼠与易患神经母细胞瘤的 Th-MYCN 小鼠杂交。虽然 MYCN 过度表达本身很少引起骨髓转移，但 MYCN 过度表达和 caspase-8 缺失相结合显着增强了骨髓转移（发生率 37%）。原发肿瘤 mRNA 和 microRNA 的微阵列表达研究揭示了细胞外基质 (ECM) 结构变化、参与上皮间质转化、炎症以及 miR-7a 和 miR-29b 下调的基因表达增加。这些分子变化已被证明与各种肿瘤模型中的肿瘤进展和细胞因子转化生长因子β（TGF-β）途径的激活有关。细胞因子 TGF-β 可以优先促进单细胞运动和血源性转移，因此该途径的激活可以解释在该动物模型中观察到的骨髓转移增强。
Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow (BM). Advances in therapy and understanding of the metastatic process have been limited due in part, to the lack of animal models harboring BM disease. The widely employed transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the BM. This model recapitulates two frequent alterations in metastatic neuroblasoma, over-expression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. While over-expression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced BM metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix (ECM) structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation and down-regulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine transforming growth factor beta (TGF-β) pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood borne metastasis and therefore activation of this pathway may explain the enhanced BM metastasis observed in this animal model.