Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y1086, c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity
Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y1086, c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity
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DOI：
10.1038/onc.2013.154
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发表时间：
2014-04-17
期刊：
影响因子：
8
通讯作者：
Oliveira, M. J.
中科院分区：
文献类型：
--
作者：
Cardoso, A. P.;Pinto, M. L.;Oliveira, M. J.
癌细胞与其微环境之间的相互作用对于恶性进展至关重要，因为它们调节与侵袭相关的活动。肿瘤相关巨噬细胞通常被认为是几种类型癌症的肿瘤进展过程中的盟友，尽管它们在胃癌和结直肠癌中的作用仍然知之甚少。在这份报告中，我们研究了原代人巨噬细胞对胃癌和结直肠癌细胞的影响，考虑了侵袭，运动/迁移，蛋白水解和激活的细胞内信号通路。我们证明，巨噬细胞刺激癌细胞的侵袭，运动和迁移，这些影响取决于基质金属蛋白酶（MMP）的活性和表皮生长因子受体（EGFR）（在残基Y-1086），PLC-γ（磷脂酶C-γ）和Gab 1（GRB 2相关的结合蛋白-1）的激活，如siRNA（小干扰RNA）实验所证明的。表皮生长因子（EGF）-免疫耗竭损害巨噬细胞介导的癌细胞侵袭和运动，表明EGF是巨噬细胞产生的促侵袭和促运动因子。巨噬细胞还诱导胃癌和结直肠癌细胞Akt、c-Src和ERK 1/2磷酸化，并导致RhoA和Cdc 42活性增加。有趣的是，尽管巨噬细胞介导的癌细胞c-Src和ERK 1/2磷酸化发生在EGFR激活的下游，Akt磷酸化似乎是一个平行的事件，以EGFR非依赖性的方式发生。表皮生长因子，表皮生长因子受体下游信号伙伴和基质金属蛋白酶在巨噬细胞介导的入侵的参与提供了新的见解之间建立的癌细胞和巨噬细胞的分子串扰，打开新的视角，设计新的和更有效的治疗策略，以对抗癌细胞的侵袭。
The interactions between cancer cells and their microenvironment are crucial for malignant progression, as they modulate invasion-related activities. Tumor-associated macrophages are generally considered allies in the process of tumor progression in several types of cancer, although their role on gastric and colorectal carcinomas is still poorly understood. In this report, we studied the influence of primary human macrophages on gastric and colorectal cancer cells, considering invasion, motility/migration, proteolysis and activated intracellular signaling pathways. We demonstrated that macrophages stimulate cancer cell invasion, motility and migration, and that these effects depend on matrix metalloproteinase (MMP) activity and on the activation of epidermal growth factor receptor (EGFR) (at the residue Y-1086), PLC-gamma (phospholipase C-gamma) and Gab1 (GRB2-associated binding protein-1), as evidenced by siRNA (small interference RNA) experiments. Epidermal growth factor (EGF)-immunodepletion impaired macrophage-mediated cancer cell invasion and motility, suggesting that EGF is the pro-invasive and pro-motile factor produced by macrophages. Macrophages also induced gastric and colorectal cancer cell phosphorylation of Akt, c-Src and ERK1/2, and led to an increase of RhoA and Cdc42 activity. Interestingly, whereas macrophage-mediated cancer cell c-Src and ERK1/2 phosphorylation occurred downstream EGFR activation, Akt phosphorylation seems to be a parallel event, taking place in an EGFR-independent manner. The involvement of EGF, EGFR-downstream signaling partners and MMPs in macrophage-mediated invasion provides novel insights into the molecular crosstalk established between cancer cells and macrophages, opening new perspectives for the design of new and more efficient therapeutic strategies to counteract cancer cell invasion.