A compact VEGF signature associated with distant metastases and poor outcomes.
A compact VEGF signature associated with distant metastases and poor outcomes.
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DOI：
10.1186/1741-7015-7-9
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发表时间：
2009-03-16
期刊：
影响因子：
9.3
通讯作者：
Perou CM
中科院分区：
文献类型：
--
作者：
Hu Z;Fan C;Livasy C;He X;Oh DS;Ewend MG;Carey LA;Subramanian S;West R;Ikpatt F;Olopade OI;van de Rijn M;Perou CM
肿瘤转移对患者的生存构成最大的威胁，因此，了解播散性癌细胞的生物学对于开发有效的治疗方法至关重要。微阵列和免疫组化被用来分析原发性乳腺肿瘤，区域（淋巴结）转移，和远处转移，以确定与远处转移相关的生物学特征。当相互比较时，原发性肿瘤和区域转移显示统计学上难以区分的基因表达模式。比较具有远处转移与原发性肿瘤或区域转移的患者的监督分析显示，远处转移是不同的，并且通过缺乏成纤维细胞/间充质基因的表达以及通过包括VEGF、ANGPTL 4、ADM和单羧酸转运蛋白SLC 16 A3的13基因谱（即，“血管内皮生长因子（VEGF）谱”）的高表达来区分。这些基因中至少有8/13个含有HIF 1 α结合位点，已知许多受HIF 1 α调节，VEGF谱的表达与HIF 1 α IHC阳性相关。VEGF谱在乳腺癌、肺癌和胶质母细胞瘤患者的测试中也显示出预后意义，并且当在包含其他预后基因表达谱和临床变量的模型中进行测试时，VEGF谱是原发性乳腺癌结局的独立预测因子。这些数据鉴定了倾向于存在于远处转移样品中的紧凑的体内缺氧特征，并且其预示着多种肿瘤类型的不良结果。这种特征表明，对缺氧的反应包括促进新的血液和淋巴管形成的能力，并且需要多种细胞类型和途径的双重靶向来防止转移扩散。
Tumor metastases pose the greatest threat to a patient's survival, and thus, understanding the biology of disseminated cancer cells is critical for developing effective therapies. Microarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases. When compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the 'vascular endothelial growth factor (VEGF) profile') that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables. These data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types. This signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, and that the dual targeting of multiple cell types and pathways will be needed to prevent metastatic spread.
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在412例患者的基于人群的队列中，乳腺癌的固有分子特征。
影响因子：
7.4
作者：
Calza, Stefano;Hall, Per;Auer, Gert;Bjohle, Judith;Klaar, Sigrid;Kronenwett, Ulrike;T Liu, Edison;Miller, Lance;Ploner, Alexander;Smeds, Johanna;Bergh, Jonas;Pawitan, Yudi
通讯作者：
Pawitan, Yudi
影响因子：
5.8
作者：
Benito, M;Parker, J;Marron, JS
通讯作者：
Marron, JS
影响因子：
9.8
作者：
Chang HY;Sneddon JB;Alizadeh AA;Sood R;West RB;Montgomery K;Chi JT;van de Rijn M;Botstein D;Brown PO
通讯作者：
Brown PO
影响因子：
50.3
作者：
Kang, YB;Siegel, PM;Massagué, J
通讯作者：
Massagué, J
影响因子：
4.4
作者：
Hu, Zhiyuan;Fan, Cheng;Perou, Charles M.
通讯作者：
Perou, Charles M.