Transcriptional Switch of Dormant Tumors to Fast-Growing Angiogenic Phenotype
Transcriptional Switch of Dormant Tumors to Fast-Growing Angiogenic Phenotype
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DOI：
10.1158/0008-5472.can-08-2590
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Abdollahi, Amir
中科院分区：
文献类型：
--
作者：
Almog, Nava;Ma, Lili;Abdollahi, Amir
肿瘤休眠对癌症的早期发现和治疗具有重要意义。缺乏实验模型和临床可获得性有限构成了休眠肿瘤分子特征的主要障碍。我们已经开发出人体肿瘤长期处于休眠状态的模型(>；120天)，直到它们转变为快速生长和强烈的血管生成。这些血管生成的肿瘤一旦注射到新的小鼠体内，就保持了快速生长的能力。我们假设，潜伏期肿瘤在向快速生长表型转变的过程中经历了稳定的基因重新编程。全基因组转录分析被用来剖析潜伏期乳腺癌、胶质母细胞瘤、骨肉瘤和脂肪肉瘤转变的分子机制。产生了区分所有四个休眠和切换的快速生长肿瘤的共识表达签名。与我们的表型观察一致，血管生成过程是对功能基因类别影响最显著的。潜伏期肿瘤的转变与血管生成抑制因子凝血酶敏感蛋白的下调和血管生成肿瘤对血管抑素敏感性的降低有关。休眠肿瘤向指数生长期肿瘤的转化还与调节和激活迄今未与肿瘤休眠过程相关的通路有关，如内皮细胞特异性分子-1，5‘-外核苷酸酶、金属蛋白酶组织抑制因子-3、表皮生长因子受体、胰岛素样生长因子受体和磷脂酰肌醇3-激酶信号转导。此外，还发现了新的休眠特异性生物标志物，如H2BK和Eph受体A5(EPHA5)。小鼠血浆EPHA5水平和脑胶质瘤患者肿瘤标本中的mRNA水平与疾病分期相关。这些数据将有助于识别新的早期癌症生物标志物，并可能为开发促进休眠的肿瘤治疗策略提供理论基础。[癌症资源2009；69(3)：836-44]
Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (>120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell-specific molecule-1, 5'-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy strategies. [Cancer Res 2009;69(3):836-44]