Lymphatic metastasis represents the main route of tumour cell dissemination in oral squamous cell carcinoma (OSCC). Yet, there are no FDA-approved therapeutics targeting cancer-related lymphangiogenesis to date. The lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), a specific lymphatic marker, is associated with poor survival in OSCC patients. In this study, we present a potential novel mechanism of lymphatic metastasis in OSCC—lymphatic mimicry (LM), a process whereby tumour cells form cytokeratin⁺/LYVE-1⁺, but podoplanin-negative, mosaic endothelial-like vessels. LM was detected in one-third (20/57; 35.08%) of randomly selected OSCC patients. The LM-positive patients had shorter overall survival (OS) compared to LM-negative group albeit not statistically significant. Highly-metastatic tumour cells formed distinct LM structures in vitro and in vivo. Importantly, the siRNA-mediated knockdown of LYVE-1 not only impaired tumour cell migration but also blunted their capacity to form LM-vessels in vitro and reduced tumour metastasis in vivo. Together, our findings uncovered, to our knowledge, a previously unknown expression and function of LYVE-1 in OSCC, whereby tumour cells could induce LM formation and promote lymphatic metastasis. Finally, more detailed studies on LM are warranted to better define this phenomenon in the future. These studies could benefit the development of targeted therapeutics for blocking tumour-related lymphangiogenesis.

淋巴转移是口腔鳞状细胞癌（OSCC）中肿瘤细胞扩散的主要途径。但是，迄今为止，尚无FDA批准的针对癌症相关淋巴管生成的疗法。淋巴管内皮透明质酸受体1（LYVE-1）是一种特定的淋巴标志物，与OSCC患者的不良生存有关。在这项研究中，我们介绍了OSCC中淋巴转移的潜在新机制-淋巴模拟（LM），肿瘤细胞形成细胞角蛋白⁺ / LYVE-1 ^+的过程，但podoplanin阴性，镶嵌内皮样血管。在随机选择的OSCC患者中，有三分之一（20/57; 35.08％）检测到LM。与LM阴性组相比，LM阳性患者的总生存期（OS）较短，尽管无统计学意义。高转移性肿瘤细胞在体外和体内均形成独特的LM结构。重要的是，LYVE-1的siRNA介导的敲低不仅损害肿瘤细胞的迁移，而且削弱了它们在体外形成LM血管的能力，并减少了体内的肿瘤转移。据我们所知，我们的发现共同揭示了LYVE-1在OSCC中的先前未知的表达和功能，从而肿瘤细胞可诱导LM形成并促进淋巴转移。最后，有必要对LM进行更详细的研究，以便将来更好地定义这种现象。