Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR
Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR
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DOI：
10.1073/pnas.0804543106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Rak, Janusz
中科院分区：
文献类型：
--
作者：
Al-Nedawi, Khalid;Meehan, Brian;Rak, Janusz
表皮生长因子受体（EGFR）在多种人类恶性肿瘤中发挥致癌作用。虽然EGFR的细胞内效应已被充分研究，但其诱导和调节肿瘤血管生成的能力尚不清楚。我们以前发现，致癌EGFR可以作为膜微泡（MV）的货物从癌细胞中脱落，这些微泡可以与其他细胞的表面相互作用。在这里，我们报告说，由携带活化EGFR的人癌细胞（A431，A549，DLD-1）产生的MV可以被培养的内皮细胞吸收，在其中它们引起EGFR依赖性反应，包括MAPK和Akt通路的活化。这些反应可以被膜联蛋白V及其同源二聚体Diannexin阻断，这两种蛋白都掩盖了MV表面的磷脂酰丝氨酸残基。有趣的是，细胞间EGFR转移还伴随着内皮细胞中VEGF表达的开始和其关键信号受体（VEGF受体-2）的自分泌激活。在小鼠A431人肿瘤异种移植物中，血管生成内皮细胞对人EGFR和磷酸化EGFR染色阳性，而用Diannexin治疗导致肿瘤生长速率和微血管密度降低。因此，我们提出，含有癌基因的肿瘤细胞衍生的MV可以作为一种独特的形式的血管生成调节刺激，并能够切换内皮细胞的自分泌模式。
Activated EGF receptor (EGFR) plays an oncogenic role in several human malignancies. Although the intracellular effects of EGFR are well studied, its ability to induce and modulate tumor angiogenesis is less understood. We found previously that oncogenic EGFR can be shed from cancer cells as cargo of membrane microvesicles (MVs), which can interact with surfaces of other cells. Here we report that MVs produced by human cancer cells harboring activated EGFR (A431, A549, DLD-1) can be taken up by cultured endothelial cells, in which they elicit EGFR-dependent responses, including activation of MAPK and Akt pathways. These responses can be blocked by annexin V and its homodimer, Diannexin, both of which cloak phosphatidylserine residues on the surfaces of MVs. Interestingly, the intercellular EGFR transfer is also accompanied by the onset of VEGF expression in endothelial cells and by autocrine activation of its key signaling receptor (VEGF receptor-2). In A431 human tumor xenografts in mice, angiogenic endothelial cells stain positively for human EGFR and phospho-EGFR, while treatment with Diannexin leads to a reduction of tumor growth rate and microvascular density. Thus, we propose that oncogene-containing tumor cell-derived MVs could act as a unique form of angiogenesis-modulating stimuli and are capable of switching endothelial cells to act in an autocrine mode.