MTDH in macrophages promotes the vasculogenic mimicry via VEGFA-165/Flt-1 signaling pathway in head and neck squamous cell carcinoma
MTDH in macrophages promotes the vasculogenic mimicry via VEGFA-165/Flt-1 signaling pathway in head and neck squamous cell carcinoma
复制标题
巨噬细胞中的MTDH通过VEGFA-165/Flt-1信号通路促进头颈鳞状细胞癌中的血管生成拟态
DOI：
10.1016/j.intimp.2021.107776
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发表时间：
2021
影响因子：
5.6
通讯作者：
Wei Xu
中科院分区：
文献类型：
--
作者：
Xiuxiu Liu;Zhenghua Lv;Shengli Zhou;Shifeng Kan;Xianfang Liu;Peihang Jing;Wei Xu
血管生成拟态（Vasculogenic mimicry，VM）是指肿瘤细胞在侵袭过程中形成的血管样结构，与肿瘤的侵袭和转移密切相关。在此，我们研究了巨噬细胞来源的MTDH对头颈部鳞状细胞癌（HNSCC）VM形成的影响及其潜在机制。MTDH过表达的巨噬细胞（Mac-MTDH）在体外可促进癌细胞VM的形成、迁移和侵袭。此外，MTDH过表达触发巨噬细胞极化为M2型肿瘤相关巨噬细胞。对HNSCC临床样本的分析显示，MTDH+巨噬细胞主要位于VM附近的肿瘤间质区域中，并且与淋巴结转移相关。在机制上，Mac-MTDH通过β-连环蛋白增强VEGFA-165而不是其它VEGFA同种型的表达和分泌。VEGFA-165/Flt-1轴通过p-STAT 3/Twist 1/VE-cadherin途径参与了Mac-MTDH在癌细胞中的作用。利用小鼠模型，我们进一步证实了Mac-MTDH在体内增加VM形成和癌转移。此外，在皮下异种移植小鼠模型中，HN 6 + Mac-MTDH肿瘤表现出比HN 6 + Mac-NC肿瘤更高的p-STAT 3和Twist 1表达。本研究表明，Mac-MTDH通过VEGFA-165/Flt-1轴促进VM形成、癌细胞迁移和侵袭以及癌转移，巨噬细胞源性MTDH可能成为HNSCC潜在的治疗靶点。
Vasculogenic mimicry (VM) refers to vessel-like structures formed by aggressive tumor cells and is closely associated with cancer invasion and metastasis. Here, we investigated the effect of macrophage-derived MTDH on VM formation in head and neck squamous cell carcinoma (HNSCC) and its underlying mechanism. Macrophages with MTDH overexpression (Mac-MTDH) promoted cancer cell VM formation, migration, and invasionin vitro. Moreover, MTDH overexpression triggered macrophage polarization into M2 type tumor-associated macrophages. Analysis of HNSCC clinical samples revealed that MTDH+macrophages were predominantly located in the tumor-stromal region in proximity to VM and correlated with lymph node metastasis. Mechanistically, Mac-MTDH enhanced the expression and secretion of VEGFA-165 rather than other VEGFA isoforms via ß-catenin. The VEGFA-165/Flt-1 axis was responsible for Mac-MTDH’s effects in cancer cells through p-STAT3/Twist1/VE-cadherin pathway. Using mouse model, we further confirmed that Mac-MTDH increased VM formation and cancer metastasisin vivo. Furthermore, in subcutaneous xenograft mouse model, HN6 + Mac-MTDH tumor exhibited elevated expression of p-STAT3 and Twist1 than HN6 + Mac-NC tumors. This study revealed that Mac-MTDH promoted VM formation, cancer cell migration and invasion, and cancer metastasis through VEGFA-165/Flt-1 axis, and that macrophage-derived MTDH could be a potential therapeutic target in HNSCC.