Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment.
Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment.
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DOI：
10.1016/j.yexcr.2014.02.020
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发表时间：
2014-04-15
影响因子：
3.7
通讯作者：
Modiano, Jaime F.
中科院分区：
文献类型：
--
作者：
Kim, Jong-Hyuk;Frantz, Aric M.;Anderson, Katie L.;Graef, Ashley J.;Scott, Milcah C.;Robinson, Sally;Sharkey, Leslie C.;O'Brien, Timothy D.;Dickerson, Erin B.;Modiano, Jaime F.
白细胞介素 - 8（IL - 8）基因在犬血管肉瘤（HSA）中高度上调；然而，其在该疾病发病机制中的作用尚不清楚。我们研究了IL - 8在犬HSA组织和细胞系中的表达，以及IL - 8在体外和体内（后者使用小鼠异种移植模型）对犬HSA的影响。IL - 8 mRNA、IL - 8蛋白和IL - 8受体的组成性表达在不同肿瘤样本和细胞系中存在差异，但在每个细胞系中呈现稳定状态。添加IL - 8后，HSA细胞出现短暂的细胞内钙流，这表明它们的IL - 8受体具有功能，并且IL - 8结合激活了相关信号通路。然而，无论是添加外源性IL - 8，还是通过中和抗IL - 8抗体（α - IL - 8 Ab）阻断内源性IL - 8，都不影响HSA细胞在体外的增殖或存活。为了评估IL - 8对其他肿瘤成分的潜在影响，我们将HSA细胞系和整个肿瘤样本分为“IL - 8高”和“IL - 8低”组。全基因组基因表达谱分析显示，“IL - 8高”肿瘤组的样本富含与“反应性微环境”相关的基因，包括凝血激活、炎症和纤维化网络。基于这些发现，我们假设IL - 8对这些肿瘤的影响大多是间接的，是通过调节与微环境的相互作用来实现的。这一假设得到了体内异种移植实验的支持，在该实验中，通过给予中和性α - IL - 8 Ab抑制了肿瘤细胞的存活和植入。总之，我们的结果表明，IL - 8在HSA肿瘤发生的早期阶段有助于建立一个适宜的微环境。
Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into “IL-8 high” and “IL-8 low” groups. Genome-wide gene expression profiling showed that samples in the “IL-8 high” tumor group were enriched for genes associated with a “reactive microenvironment,” including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA.
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影响因子：
8.8
作者：
Lee, Y. S.;Choi, I.;Ning, Y.;Kim, N. Y.;Khatchadourian, V.;Yang, D.;Chung, H. K.;Choi, D.;LaBonte, M. J.;Ladner, R. D.;Venkata, K. C. Nagulapalli;Rosenberg, D. O.;Petasis, N. A.;Lenz, H-J;Hong, Y-K
通讯作者：
Hong, Y-K
影响因子：
20.3
作者：
Kryczek, Ilona;Banerjee, Mousumi;Zou, Weiping
通讯作者：
Zou, Weiping
影响因子：
5.7
作者：
Medina, Reinhold J.;O'Neill, Christina L.;Stitt, Alan W.
通讯作者：
Stitt, Alan W.
影响因子：
3.8
作者：
Gangadharan, Charitha;Thoh, Maikho;Manna, Sunil Kumar
通讯作者：
Manna, Sunil Kumar
影响因子：
4.8
作者：
Akhtar, N;Padilla, ML;Helfand, SC
通讯作者：
Helfand, SC