Department of Otorhinolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Shandong Provincial Key Laboratory of Otology, Jinan, Shandong, China.
Department of Otorhinolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Shandong Provincial Key Laboratory of Otology, Jinan, Shandong, China.
Int Immunopharmacol. 2021 Jul;96:107776. doi: 10.1016/j.intimp.2021.107776. Epub 2021 May 24.
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 invasion in 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 metastasis in 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.
血管生成拟态（VM）是指由侵袭性肿瘤细胞形成的类似血管的结构，与癌症的侵袭和转移密切相关。在这里，我们研究了巨噬细胞衍生的 MTDH 对头颈鳞状细胞癌（HNSCC）中 VM 形成的影响及其潜在机制。过表达 MTDH 的巨噬细胞（Mac-MTDH）促进了体外癌细胞 VM 的形成、迁移和侵袭。此外，MTDH 的过表达触发了巨噬细胞向 M2 型肿瘤相关巨噬细胞的极化。对 HNSCC 临床样本的分析表明，MTDH 巨噬细胞主要位于肿瘤基质区域，靠近 VM，并与淋巴结转移相关。在机制上，Mac-MTDH 通过β-catenin 增强了 VEGFA-165 的表达和分泌，而不是其他 VEGFA 同工型。VEGFA-165/Flt-1 轴通过 p-STAT3/Twist1/VE-cadherin 通路负责 Mac-MTDH 在癌细胞中的作用。通过小鼠模型，我们进一步证实了 Mac-MTDH 在体内增加了 VM 的形成和癌症转移。此外，在皮下异种移植小鼠模型中，与 HN6+Mac-NC 肿瘤相比，HN6+Mac-MTDH 肿瘤表现出更高的 p-STAT3 和 Twist1 表达。这项研究表明，Mac-MTDH 通过 VEGFA-165/Flt-1 轴促进 VM 的形成、癌细胞的迁移和侵袭以及癌症的转移，并且巨噬细胞衍生的 MTDH 可能是 HNSCC 的一个潜在治疗靶点。
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