Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion.
Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion.
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DOI：
10.1007/s10456-011-9241-1
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发表时间：
2012-03
期刊：
影响因子：
9.8
通讯作者：
Kohn, Elise C.
中科院分区：
文献类型：
--
作者：
Mineo, Marco;Garfield, Susan H.;Taverna, Simona;Flugy, Anna;De Leo, Giacomo;Alessandro, Riccardo;Kohn, Elise C.
外体是由正常细胞和肿瘤细胞释放的内源性微囊，在细胞间的通讯中起着重要的作用。血管生成对慢性粒细胞白血病(CML)的进展有调节作用。这种情况发生的机制还没有被阐明。我们从K562慢性粒细胞白血病细胞中分离和鉴定了外切体，并评价了它们对人脐静脉内皮细胞的作用。在Matrigel上的小管分化过程中，荧光标记的外切体被HUVECs内化。外切小体定位于分化早期的核周，在细胞伸长和连接过程中沿外围移动。外切体在连接重塑的内皮细胞的纳米管结构内和之间移动。在血清/生长因子限制的培养液对照中，它们刺激了血管管的形成，使总累积管长增加了一倍(P=0.003)。用两种临床活性酪氨酸激酶抑制剂伊马替尼和达沙替尼处理K562细胞，减少了它们的总外切体释放(P<；0.009)；同等浓度的药物处理的外切体诱导了类似程度的小管分化。然而，达沙替尼显著抑制血管内皮细胞对药物对照慢性粒细胞白血病外切体的反应(P<；0.002)。在小鼠体内Matrigel Plug模型中，K562外切体能诱导血管生成，口服达沙替尼可抑制血管生成(P<；0.01)。K562外切体诱导人脐静脉内皮细胞对达沙替尼敏感的Src磷酸化并激活其下游的Src途径蛋白。伊马替尼对外切体刺激人脐静脉内皮细胞分化和信号传导的作用最小。因此，慢性粒细胞白血病细胞来源的外切体在HUVEC细胞中诱导血管生成活性。达沙替尼对外切体产生、血管分化和信号转导的抑制作用揭示了Src在白血病及其微环境中的关键作用。
Exosomes, microvesicles of endocytic origin released by normal and tumor cells, play an important role in cell-to-cell communication. Angiogenesis has been shown to regulate progression of chronic myeloid leukemia (CML). The mechanism through which this happens has not been elucidated. We isolated and characterized exosomes from K562 CML cells and evaluated their effects on human umbilical endothelial cells (HUVECs). Fluorescent-labeled exosomes were internalized by HUVECs during tubular differentiation on Matrigel. Exosome localization was perinuclear early in differentiation, moving peripherally in cells undergoing elongation and connection. Exosomes move within and between nanotubular structures connecting the remodeling endothelial cells. They stimulated angiotube formation over a serum/growth factor-limited medium control, doubling total cumulative tube length (P = 0.003). Treatment of K562 cells with two clinically active tyrosine kinase inhibitors, imatinib and dasatinib, reduced their total exosome release (P <0.009); equivalent concentrations of drug-treated exosomes induced a similar extent of tubular differentiation. However, dasatinib treatment of HUVECs markedly inhibited HUVEC response to drug control CML exosomes (P <0.002). In an in vivo mouse Matrigel plug model angiogenesis was induced by K562 exosomes and abrogated by oral dasatinib treatment (P <0.01). K562 exosomes induced dasatinib-sensitive Src phosphorylation and activation of downstream Src pathway proteins in HUVECs. Imatinib was minimally active against exosome stimulation of HUVEC cell differentiation and signaling. Thus, CML cell-derived exosomes induce angiogenic activity in HUVEC cells. The inhibitory effect of dasatinib on exosome production and vascular differentiation and signaling reveals a key role for Src in both the leukemia and its microenvironment.
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影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
4.8
作者：
Savina, A;Furl치n, M;Colombo, MI
通讯作者：
Colombo, MI
影响因子：
20.3
作者：
Legros, L;Bourcier, C;Pagès, G
通讯作者：
Pagès, G
影响因子：
7.5
作者：
Gerdes, Hans-Hermann;Carvalho, Raquel Negrao
通讯作者：
Carvalho, Raquel Negrao
影响因子：
21.3
作者：
Skog, Johan;Wuerdinger, Tom;van Rijn, Sjoerd;Meijer, Dimphna H.;Gainche, Laura;Sena-Esteves, Miguel;Curry, William T., Jr.;Carter, Bob S.;Krichevsky, Anna M.;Breakefield, Xandra O.
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Breakefield, Xandra O.