HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
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DOI：
10.1007/s10456-013-9363-8
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发表时间：
2013-10-01
期刊：
影响因子：
9.8
通讯作者：
Olsson, Anna-Karin
中科院分区：
文献类型：
--
作者：
Cedervall, Jessica;Zhang, Yanyu;Olsson, Anna-Karin
缺乏富含组氨酸的糖蛋白（HRG）的小鼠表现出加速的血管生成转换和更大的肿瘤——这是由缺乏HRG的小鼠中血小板活化增强引起的表型。在这里，我们发现血小板在 HRG 缺陷小鼠中诱导肿瘤发生前环境的分子变化，促进细胞存活、血管生成和上皮间质转化 (EMT)，并且这些效应涉及通过 TBK1、Akt2 和 PDGFR beta 的信号传导。这些早期事件随后转化为缺乏 HRG 的小鼠向远处器官自发转移率的提高。在肿瘤发展后期，病理性血管生成的特征，例如灌注和周细胞覆盖减少，在 HRG 缺陷小鼠中更为明显。在此阶段，血小板对于维持缺乏 HRG 的小鼠的肿瘤脉管系统的充分功能来支持其形成的较大肿瘤体积至关重要。我们得出的结论是，HRG 缺陷通过增强血小板活性促进肿瘤进展，并且血小板在此过程中发挥双重作用。在转化的早期阶段，活化的血小板促进肿瘤细胞存活、血管生成转换和侵袭。在进展较严重的肿瘤中，血小板支持增强的病理性血管生成，因此在没有 HRG 的情况下会增加肿瘤生长。总而言之，我们的研究结果强化了 HRG 作为一种有效的肿瘤抑制剂的概念，能够通过调节血小板活性来减弱血管生成开关、肿瘤生长、EMT 和随后的转移扩散。
Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFR beta. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.