Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma.
Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma.
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DOI：
10.1371/journal.pone.0019103
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Montaner S
中科院分区：
文献类型：
--
作者：
Jham BC;Ma T;Hu J;Chaisuparat R;Friedman ER;Pandolfi PP;Schneider A;Sodhi A;Montaner S
卡波西肉瘤是一种血管性肿瘤，其特征是血管生成和炎性细胞因子的表达失调。KS病变的驱动力，KSHV感染的梭形细胞，分泌血管内皮生长因子（VEGF），KS发展所必需的水平升高。然而，VEGF在该肿瘤中的起源仍不清楚。在这里，我们报告说，KSHV G蛋白偶联受体（vGPCR）上调血管内皮生长因子在KS通过一个复杂的旁分泌机制。由少数表达vGPCR的肿瘤细胞分泌的细胞因子在邻近细胞中激活多种途径（包括AKT、ERK、p38和IKKβ），这些途径进而会聚在TSC 1/2上，促进mTOR激活、HIF上调和VEGF分泌。来自vGPCR表达细胞的条件培养基导致HIF-1α和HIF-2α蛋白水平的mTOR依赖性增加以及VEGF上调。在KS的小鼠同种异体移植模型中，特异性抑制非vGPCR表达细胞中mTOR的旁分泌激活足以抑制这些细胞中HIF上调，并消除vGPCR表达细胞促进体内肿瘤形成的能力。类似地，在该模型中HIF的药理学抑制阻断了VEGF分泌并且也导致肿瘤消退。我们的研究结果提供了一个令人信服的解释，少数肿瘤细胞表达vGPCR可以有助于显着放大血管内皮生长因子分泌KS，并进一步提供了一个分子机制，如何在KS细胞因子失调燃料血管生成和肿瘤的发展。这些数据进一步表明，通过vGPCR激活HIF可能是治疗KS患者的一个易受攻击的靶点。
Kaposi's sarcoma (KS) is a vascular neoplasm characterized by the dysregulated expression of angiogenic and inflammatory cytokines. The driving force of the KS lesion, the KSHV-infected spindle cell, secretes elevated levels of vascular endothelial growth factor (VEGF), essential for KS development. However, the origin of VEGF in this tumor remains unclear. Here we report that the KSHV G protein-coupled receptor (vGPCR) upregulates VEGF in KS through an intricate paracrine mechanism. The cytokines secreted by the few vGPCR-expressing tumor cells activate in neighboring cells multiple pathways (including AKT, ERK, p38 and IKKβ) that, in turn, converge on TSC1/2, promoting mTOR activation, HIF upregulation, and VEGF secretion. Conditioned media from vGPCR-expressing cells lead to an mTOR-dependent increase in HIF-1α and HIF-2α protein levels and VEGF upregulation. In a mouse allograft model for KS, specific inhibition of the paracrine activation of mTOR in non-vGPCR-expressing cells was sufficient to inhibit HIF upregulation in these cells, and abolished the ability of the vGPCR-expressing cells to promote tumor formation in vivo. Similarly, pharmacologic inhibition of HIF in this model blocked VEGF secretion and also lead to tumor regression. Our findings provide a compelling explanation for how the few tumor cells expressing vGPCR can contribute to the dramatic amplification of VEGF secretion in KS, and further provide a molecular mechanism for how cytokine dysregulation in KS fuels angiogenesis and tumor development. These data further suggest that activation of HIF by vGPCR may be a vulnerable target for the treatment of patients with KS.
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影响因子：
5.4
作者：
Cai, Qiliang;Murakami, Masanao;Robertson, Erle S.
通讯作者：
Robertson, Erle S.
影响因子：
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作者：
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DOI：
10.1073/pnas.94.3.979
发表时间：
1997-02-04
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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