Protumoral bone marrow-derived cells migrate via G-dependent signaling pathways and exhibit a complex repertoire of RhoGEFs
Protumoral bone marrow-derived cells migrate via G-dependent signaling pathways and exhibit a complex repertoire of RhoGEFs
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DOI：
10.1007/s12079-018-00502-6
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发表时间：
2019-06-01
影响因子：
4.1
通讯作者：
Vazquez-Prado, Jose
中科院分区：
文献类型：
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作者：
Daniel Cervantes-Villagrana, Rodolfo;Manuel Color-Aparic, Victor;Vazquez-Prado, Jose
肿瘤微环境中细胞之间的相互交流有助于癌症进展。在这里，我们表明，一个protumoral人口培养的骨髓来源的细胞（BMDC）Tie 2 +/CD 45 +/CD 11b+细胞对肺癌细胞的反应，并刺激他们。这些细胞通过异源三聚体G蛋白依赖性信号通路迁移，并强烈激活PI 3 K/AKT，ERK和mTOR信号级联反应的条件培养基和趋化性激动剂。为了深入了解参与BMDC迁移的分子机制，我们揭示了与新鲜骨髓细胞相比，Rho GTPases（RhoGEFs）和G蛋白的鸟嘌呤核苷酸交换因子的库，证明这些细胞群对肿瘤生长具有对比效应。BMDC中G蛋白调节的RhoGEFs表达量较高，包括P-Rex 1、PDZ-RhoGEF、LARG、Trio和一些不太清楚的RhoGEFs如ARHGEF 5、ARHGEF 17和PLEKHG 6。G蛋白如G（12/13）、G（q）和小G蛋白RhoJ也在BMDC中高度表达。我们的研究结果表明，Tie 2 +/CD 45 +/CD 11b +BMDC表达一种独特的多种趋化性转换器和效应器，可能与其促肿瘤作用有关，从而进一步研究其作为分子靶点的特征。
Reciprocal communication among cells of the tumor microenvironment contributes to cancer progression. Here, we show that a protumoral population of cultured bone marrow-derived cells (BMDC) containing Tie2+/CD45+/CD11b+cells responded to lung carcinoma cells and reciprocally stimulated them. These cells migrated via heterotrimeric G protein-dependent signaling pathways and strongly activated the PI3K/AKT, ERK and mTOR signaling cascades in response to conditioned media and chemotactic agonists. To get insight into the molecular machinery involved in BMDC migration, we revealed their repertoire of guanine nucleotide exchange factors for Rho GTPases (RhoGEFs) and G proteins in comparison with fresh bone marrow cells, proven that these cell populations had contrasting effects on tumor growth. BMDC exhibited a higher expression of G protein regulated RhoGEFs including P-Rex1, PDZ-RhoGEF, LARG, Trio and some less well characterized RhoGEFs such as ARHGEF5, ARHGEF17 and PLEKHG6. G proteins such as G(12/13), G(q), and the small GTPase RhoJ were also highly expressed in BMDC. Our results indicate that Tie2+/CD45+/CD11b+BMDC express a unique variety of chemotactic transducers and effectors potentially linked to their protumoral effect, warranting further studies to their characterization as molecular targets.