ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling.
ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling.
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DOI：
10.1158/1541-7786.mcr-17-0188
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Moses MA
中科院分区：
文献类型：
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作者：
Roy R;Dagher A;Butterfield C;Moses MA
ADAM 12（一种含有去整合素和金属蛋白酶结构域的蛋白12）在上皮癌中上调，并有助于增加肿瘤增殖、转移和内分泌抵抗。然而，其在肿瘤血管生成中的作用尚不清楚。在这里，我们报告ADAM 12在侵袭性乳腺肿瘤的血管中上调，并发挥关键的调节功能。ADAM 12在体内显著增加bFGF介导的血管生成，并且ADAM 12水平在已经经历血管生成表型转换的肿瘤中上调。重要的是，ADAM 12过表达的乳腺肿瘤显示出更高的微血管密度（MVD）。我们的目的是确定肿瘤相关的ADAM 12促进血管生成的机制。乳腺肿瘤细胞中的ADAM 12表达与促血管生成因子如VEGF和MMP-9的显著上调以及抗血管生成因子如血小板反应蛋白-1（THBS 1/TSP 1）和金属蛋白酶组织抑制剂-2（TIMP-2）的下调相关。与表达ADAM 12的肿瘤细胞共培养促进了内皮细胞（EC）的募集和毛细血管的形成。相反，乳腺癌细胞系中内源性ADAM 12的下调导致促血管生成因子和EC募集的减少。这些ADAM 12介导的作用是由EGFR、STAT 3和Akt信号传导的激活驱动的。阻断EGFR/STAT 3或沉默ADAM 12逆转了促血管生成肿瘤表型，显著下调促血管生成有丝分裂原，减少EC募集。在人乳腺癌组织中，ADAM 12的表达与促血管生成因子VEGF和MMP-9呈显著正相关，而与TSP 1呈负相关。
ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our aim was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue inhibitor of metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.