Laboratoire d'Oncologie Moléculaire, Centre de Recherche BIOMED, Département de Chimie, Université du Québec à Montreal, Montreal, Quebec, Canada H3C 3P8.
J Biol Chem. 2013 May 10;288(19):13378-86. doi: 10.1074/jbc.M113.456533. Epub 2013 Apr 2.
CSF-2 and CSF-3 confer proangiogenic and immunomodulatory properties to mesenchymal stromal cells (MSCs).
Transcriptional regulation of CSF-2 and CSF-3 in concanavalin A-activated MSCs requires MT1-MMP signaling and is inhibited by EGCG.
The chemopreventive properties of diet-derived EGCG alter MT1-MMP-mediated intracellular signaling.
Pharmacological targeting of MSCs proangiogenic functions may prevent their contribution to tumor development. Epigallocatechin gallate (EGCG), a major form of tea catechins, possesses immunomodulatory and antiangiogenic effects, both of which contribute to its chemopreventive properties. In this study, we evaluated the impact of EGCG treatment on the expression of colony-stimulating factors (CSF) secreted from human bone marrow-derived mesenchymal stromal cells (MSCs), all of which also contribute to the immunomodulatory and angiogenic properties of these cells. MSCs were activated with concanavalin A (ConA), a Toll-like receptor (TLR)-2 and TLR-6 agonist as well as a membrane type 1 matrix metalloproteinase (MT1-MMP) inducer, which increased granulocyte macrophage-CSF (GM-CSF, CSF-2), granulocyte CSF (G-CSF, CSF-3), and MT1-MMP gene expression. EGCG antagonized the ConA-induced CSF-2 and CSF-3 gene expression, and this process required an MT1-MMP-mediated sequential activation of the Src and JAK/STAT pathways. Gene silencing of MT1-MMP expression further demonstrated its requirement in the phosphorylation of Src and STAT3, whereas overexpression of a nonphosphorylatable MT1-MMP mutant (Y573F) abrogated CSF-2 and CSF-3 transcriptional increases. Given that MSCs are recruited within vascularizing tumors and are believed to contribute to tumor angiogenesis, possibly through secretion of CSF-2 and CSF-3, our study suggests that diet-derived polyphenols such as EGCG may exert chemopreventive action through pharmacological targeting of the MT1-MMP intracellular signaling.
CSF-2 和 CSF-3 赋予间充质基质细胞（MSCs）促血管生成和免疫调节特性。
刀豆球蛋白 A 激活的 MSCs 中 CSF-2 和 CSF-3 的转录调控需要 MT1-MMP 信号，而 EGCG 可抑制其表达。
饮食中 EGCG 的化学预防特性改变了 MT1-MMP 介导的细胞内信号转导。
靶向 MSC 的促血管生成功能可能会阻止其促进肿瘤发展。表没食子儿茶素没食子酸酯（EGCG）是茶儿茶素的主要形式，具有免疫调节和抗血管生成作用，这两者都有助于其化学预防特性。在这项研究中，我们评估了 EGCG 处理对人骨髓来源的间充质基质细胞（MSCs）分泌集落刺激因子（CSF）表达的影响，所有这些都有助于这些细胞的免疫调节和血管生成特性。MSCs 用刀豆球蛋白 A（ConA）激活，ConA 是 Toll 样受体（TLR）-2 和 TLR-6 激动剂，也是膜型 1 基质金属蛋白酶（MT1-MMP）诱导剂，可增加粒细胞巨噬细胞集落刺激因子（GM-CSF，CSF-2）、粒细胞集落刺激因子（G-CSF，CSF-3）和 MT1-MMP 基因表达。EGCG 拮抗 ConA 诱导的 CSF-2 和 CSF-3 基因表达，此过程需要 MT1-MMP 介导的Src 和 JAK/STAT 通路的顺序激活。MT1-MMP 表达的基因沉默进一步证明了其在 Src 和 STAT3 磷酸化中的必要性，而非磷酸化 MT1-MMP 突变体（Y573F）的过表达则消除了 CSF-2 和 CSF-3 转录的增加。鉴于 MSCs 可在血管生成肿瘤中招募，并被认为通过分泌 CSF-2 和 CSF-3 促进肿瘤血管生成，我们的研究表明，饮食中多酚类物质如 EGCG 可能通过靶向 MT1-MMP 细胞内信号转导发挥化学预防作用。
