KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis.
KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis.
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DOI：
10.1371/journal.ppat.1007175
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发表时间：
2018-07
期刊：
影响因子：
6.7
通讯作者：
Mesri EA
中科院分区：
文献类型：
--
作者：
Cavallin LE;Ma Q;Naipauer J;Gupta S;Kurian M;Locatelli P;Romanelli P;Nadji M;Goldschmidt-Clermont PJ;Mesri EA
卡波西肉瘤（KS）疱疹病毒（KSHV）通过自分泌和旁分泌机制激活宿主致癌信号级联，导致KS，一种血管生成性AIDS相关梭形细胞肿瘤。酪氨酸激酶受体（RTK）蛋白质组学阵列，确定PDGF受体-α（PDGFRA）为KSHV诱导的小鼠KS肿瘤中主要激活的RTK。我们证明：1）KSHV裂解性复制和vGPCR可以通过上调其配体PDGFA/B来激活PDGFRA，这增加了感染细胞中c-myc、VEGF和KSHV基因的表达2）大多数AIDS-KS病变的KSHV感染的梭形细胞显示出强烈的磷酸-PDGFRA染色3）用N-乙酰半胱氨酸、RTK抑制剂伊马替尼和舒尼替尼阻断PDGFRA信号传导，4）PDGFRA D842 V激活突变在小鼠KS肿瘤发生中赋予对伊马替尼的抗性。我们的数据表明，KSHV篡夺肉瘤原PDGFRA信号驱动KS。这一点以及PDGFRA驱动非病毒肉瘤的事实凸显了KSHV诱导的配体介导的PDGFRA激活在KS肉瘤发生中的重要性，并表明可以成功阻断该致癌轴以阻止KS肿瘤生长。信号模拟是肿瘤病毒能够篡夺宿主调节途径导致获得组织特异性癌症标志的关键机制。在KS领域的一个关键问题是识别由KSHV激活的这种宿主途径，这可以为KSHV病理生物学提供新的见解，阐明新的可药用途径。在这里，我们表明，KSHV裂解复制以及KSHV-癌基因vGPCR激活PDGFRA信号通过上调其配体PDGFA/B，并认为PDGFRA信号的阻断是抗肿瘤的。这表明，完全和稳定地抑制PDGFR信号传导的方法可以导致KS的成功治疗，从而验证该受体-配体信号传导轴作为治疗靶点。
Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth. Signaling mimicry is a key mechanism whereby oncoviruses can usurp host-regulatory pathways leading to acquisition of tissue-specific cancer hallmarks. A critical question in the KS field is the identification of this host pathways activated by KSHV that could provide novel insights on KSHV-pathobiology, elucidating new druggable pathways. Here we show that KSHV lytic replication as well as the KSHV-oncogene vGPCR activates PDGFRA signaling through upregulation of its ligands PDGFA/B, and that blocking of PDGFRA signaling is anti-tumorigenic. This indicates that approaches that fully and stably inhibit PDGFR-signaling could lead to successful treatments for KS, validating this receptor-ligand signaling-axis as a therapeutic target.
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影响因子：
45.3
作者：
Heinrich, MC;Corless, CL;Fletcher, JA
通讯作者：
Fletcher, JA
影响因子：
15.9
作者：
Ganem, Don
通讯作者：
Ganem, Don
影响因子：
6.4
作者：
Hosseinipour, Mina C.;Sweet, Kristen M.;Dittmer, Dirk P.
通讯作者：
Dittmer, Dirk P.
DOI：
10.1097/qad.0000000000000682
发表时间：
2015-06-19
期刊：
AIDS (London, England)
影响因子：
--
作者：
Labo N;Miley W;Benson CA;Campbell TB;Whitby D
通讯作者：
Whitby D
影响因子：
20.3
作者：
Liu, Ren;Li, Xiuqing;Gill, Parkash S.
通讯作者：
Gill, Parkash S.