A mouse model recapitulating molecular features of human mesothelioma
A mouse model recapitulating molecular features of human mesothelioma
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DOI：
10.1158/0008-5472.can-05-2312
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Testa, JR
中科院分区：
文献类型：
--
作者：
Altomare, DA;Vaslet, CA;Testa, JR
恶性间皮瘤与石棉暴露有关，并且通常预后不良，因为它通常在晚期被诊断出来，并且对常规治疗无效。人类恶性间皮瘤积累多种体细胞遗传改变，包括NF 2和CDKN 2A/ARF肿瘤抑制基因的失活。为了更好地理解NF 2失活在恶性间皮瘤中的意义，并鉴定在恶性间皮瘤发病机制中与NF 2功能丧失协同作用的肿瘤抑制基因改变，我们用石棉处理Nf 2（+/-）敲除小鼠以诱导恶性间皮瘤。与石棉处理的野生型（WT）同窝仔相比，石棉暴露的Nf 2（+/-）小鼠表现出明显加速的恶性间皮瘤肿瘤形成。在Nf 2（+/-）小鼠的所有9个石棉诱导的恶性间皮瘤和暴露于石棉的WT小鼠的50%的恶性间皮瘤中观察到WT Nf 2等位基因的丢失，导致双等位基因失活。为了与鼠模型进行详细比较，还对一系列人恶性间皮瘤样品进行了DNA分析。值得注意的是，类似于人类恶性间皮瘤，来自Nf 2（+/-）小鼠的肿瘤显示Cdkn 2a/ Arf基因座和相邻Cdkn 2b肿瘤抑制基因的频繁同源缺失，以及保留Arf基因座的肿瘤亚组中Tp 53的相互失活。与人类疾病对应物一样，来自Nf 2（+/-）小鼠的恶性间皮瘤也显示Akt激酶的频繁激活，Akt激酶在肿瘤发生和治疗抗性中起核心作用。因此，这种环境致癌的小鼠模型忠实地再现了人类恶性间皮瘤的许多分子特征，并对恶性间皮瘤发病机制的进一步表征和新型治疗方式的临床前测试具有重要意义。
Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/ Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities.