Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis
Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis
复制标题
DOI：
10.1159/000438604
复制
发表时间：
2016-01-01
影响因子：
--
通讯作者：
Becker, Katrin Anne
中科院分区：
文献类型：
--
作者：
Carpinteiro, Alexander;Beckmann, Nadine;Becker, Katrin Anne
背景资料：恶性肿瘤细胞的血行转移是一个多步骤的过程，需要肿瘤细胞从局部肿瘤块释放，肿瘤细胞与血液中的血小板相互作用，以及活化的肿瘤细胞或血小板和肿瘤细胞的复合物粘附到靶器官的内皮细胞。我们以前已经表明，黑色素瘤细胞与血小板的相互作用的结果在释放酸性鞘磷脂酶（Asm）从活化的血小板。分泌的血小板衍生的Asm作用于恶性肿瘤细胞以聚集和激活整合素;这种聚集和激活对于肿瘤细胞粘附至内皮细胞和转移是必需的。研究方法：我们研究了肿瘤细胞对细胞外鞘磷脂酶治疗或与野生型和Asm缺陷型血小板共孵育的反应。我们确定了几种细胞内信号分子的磷酸化和活化，特别是p38激酶（p38K），磷脂酶C γ（PLC γ），埃兹蛋白和细胞外信号调节激酶。结果如下：B16 F10黑色素瘤细胞与Asm一起孵育可激活p38 MAP激酶（p38 K）、磷脂酶C γ（PLC γ）、埃兹蛋白和细胞外信号调节激酶。B16 F10黑色素瘤细胞与野生型或Asm缺陷型血小板的共孵育表明，p38 K的磷酸化/活化依赖于Asm。药理学阻断p38K可防止β 1整合素的激活和体外粘附。最重要的是，抑制B16 F10黑色素瘤细胞中的p38 K活性可以防止体内肿瘤细胞粘附和转移到肺部，这一发现表明p38 K对于转移的重要性。结论：肿瘤细胞与血小板接触后，活化血小板分泌Asm，可诱导肿瘤细胞p38K磷酸化。这反过来又刺激β 1整合素活化，这是肿瘤细胞粘附和随后转移所必需的。因此，抑制p38K可能是一个新的靶点，以防止肿瘤转移。(C)2016作者（s）由S. Karger AG，巴塞尔
Background: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. Methods: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase C gamma (PLC gamma), ezrin, and extracellular signal-regulated kinases. Results: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase C gamma (PLC gamma), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of beta 1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. Conclusions: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates beta 1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis. (C) 2016 The Author(s) Published by S. Karger AG, Basel