Role of the EGFR Ligand/Receptor System in the Secretion of Angiogenic Factors in Mesenchymal Stem Cells
Role of the EGFR Ligand/Receptor System in the Secretion of Angiogenic Factors in Mesenchymal Stem Cells
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DOI：
10.1002/jcp.22548
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发表时间：
2011-08-01
影响因子：
5.6
通讯作者：
Normanno, Nicola
中科院分区：
文献类型：
--
作者：
De Luca, Antonella;Gallo, Marianna;Normanno, Nicola
越来越多的证据表明，骨髓来源的间充质干细胞（MSC）被招募到发展中肿瘤的基质中，在那里它们有助于癌症的进展。MSC产生不同的生长因子，维持肿瘤相关的新血管生成。由于大多数癌分泌表皮生长因子受体（EGFR）的配体，我们评估了EGFR信号在调节MSC中血管生成因子释放中的作用。用转化生长因子α（TGF-α）（EGFR的主要配体之一）处理人原代MSC和人成骨细胞系hFOB，显著诱导该受体和不同细胞内信号传导蛋白（包括PI 3 K/AKT和MEK/MAPK途径）的活化。TGF-α诱导MSC和hFOB中血管内皮生长因子分泌水平的显著增加。与来自未处理细胞的培养基相比，来自TGF-α处理的MSC的条件培养基显示出更高的体内血管生成效果。用TGF-α处理MSC还显著增加了其他血管生成生长因子的分泌，如血管生成素-2、粒细胞集落刺激因子、肝细胞生长因子、白细胞介素（IL）-6、IL-8和血小板衍生生长因子-BB。使用选择性MEK和PI 3 K抑制剂，我们发现MEK/MAPK和PI 3 K/AKT信号通路都介导TGF-α诱导MSC分泌血管生成因子的能力。最后，用TGF-α刺激增加了MSC诱导MCF-7乳腺癌细胞迁移的能力。这些数据表明，EGFR信号调节MSC的能力，通过释放生长因子，促进新血管生成和肿瘤细胞迁移，以维持癌症进展。J.细胞。226：2131-2138，2011。(C)2010 Wiley-Liss，Inc.
Increasing evidence suggests that bone marrow-derived mesenchymal stem cells (MSCs) are recruited into the stroma of developing tumors where they contribute to cancer progression. MSCs produce different growth factors that sustain tumor-associated neo-angiogenesis. Since the majority of carcinomas secrete ligands of the epidermal growth factor receptor (EGFR), we assessed the role of EGFR signaling in regulating the release of angiogenic factors in MSCs. Treatment of human primary MSCs and of the human osteoblastic cell line hFOB with transforming growth factor alpha (TGF-alpha), one of the main ligands of the EGFR, significantly induced activation of this receptor and of different intracellular signaling proteins, including the PI3K/AKT and the MEK/MAPK pathways. TGF-alpha induced a significant increase in the levels of secretion of vascular endothelial growth factor in both MSCs and hFOB. Conditioned medium from TGF-alpha treated MSCs showed an higher in vivo angiogenic effect as compared with medium from untreated cells. Treatment of MSCs with TGF-alpha also produced a significant increase in the secretion of other angiogenic growth factors such as angiopoietin-2, granulocyte-colony stimulating factor, hepatocyte growth factor, interleukin (IL)-6, IL-8, and platelet-derived growth factor-BB. Using selective MEK and PI3K inhibitors, we found that both MEK/MAPK and the PI3K/AKT signaling pathways mediate the ability of TGF-alpha to induce secretion of angiogenic factors in MSCs. Finally, stimulation with TGF-alpha increased the ability of MSCs to induce migration of MCF-7 breast cancer cells. These data suggest that EGFR signaling regulates the ability of MSCs to sustain cancer progression through the release of growth factors that promote neo-angiogenesis and tumor cell migration. J. Cell. Physiol. 226: 2131-2138, 2011. (C) 2010 Wiley-Liss, Inc.