Downregulation of adaptor protein MyD88 compromises the angiogenic potential of B16 murine melanoma

The mechanisms that link inflammatory responses to cancer development remain a subject of intense investigation, emphasizing the need to better understand the cellular and molecular pathways that create a tumor promoting microenvironment. The myeloid differentiation primary response protein MyD88 acts as a main adaptor molecule for the signaling cascades initiated from Toll-like receptors (TLRs) and the interleukin 1 receptor (IL-1R). MyD88 has been shown to contribute to tumorigenesis in many inflammation-associated cancer models. In this study, we sought to better define the role of MyD88 in neoplastic cells using a murine melanoma model. Herein, we have demonstrated that MyD88 expression is required to maintain the angiogenic switch that supports B16 melanoma growth. By knocking down MyD88 we reduced TLR-mediated NF-κB activation with no evident effects over cell proliferation and survival. In addition, MyD88 downregulation was associated with a decrease of HIF1α levels and its target gene VEGF, in correlation with an impaired capability to induce capillary sprouting and tube formation of endothelial cells. Melanomas developed from cells lacking MyD88 showed an enhanced secretion of chemoattractant ligands such as CCL2, CXCL10 and CXCL1 and have an improved infiltration of macrophages to the tumor site. Our results imply that cell-autonomous signaling through MyD88 is required to sustain tumor growth and underscore its function as an important positive modulator of tumor angiogenesis.

炎症反应与癌症发生之间的关联机制仍是当前研究的热点方向，这凸显了深入解析促肿瘤微环境形成的细胞与分子通路的迫切需求。髓系分化初级应答蛋白88（MyD88）是Toll样受体（TLRs）与白细胞介素1受体（IL-1R）介导的信号级联反应的核心衔接分子。已有研究证实，MyD88在多种炎症相关癌症模型中可促进肿瘤发生。本研究借助小鼠黑色素瘤模型，旨在进一步明确MyD88在肿瘤细胞中的具体功能。本研究证实，MyD88的表达是维持支持B16黑色素瘤生长的血管生成开关的必要条件。通过敲低MyD88的表达，我们可抑制TLR介导的核因子κB（NF-κB）激活，且对细胞增殖与存活无显著影响。此外，MyD88下调会伴随缺氧诱导因子1α（HIF1α）及其靶基因血管内皮生长因子（VEGF）水平的降低，这与内皮细胞诱导毛细血管出芽及管腔形成的能力受损密切相关。由MyD88缺失的细胞形成的黑色素瘤，其趋化配体（如CCL2、CXCL10及CXCL1）的分泌水平显著升高，且肿瘤部位的巨噬细胞浸润程度增强。本研究结果表明，依赖MyD88的细胞自主性信号通路对维持肿瘤生长至关重要，同时证实了其作为肿瘤血管生成重要正向调控因子的功能。