FOXF2抑制基底样乳腺癌淋巴管生成拟态的作用和机制

Lymphatic metastasis is the chief pathway of breast cancer metastasis, and tumor lymphangiogenesis facilitates lymphatic metastasis of breast cancer cells. However, the mechanism of tumor lymphangiogenesis is still largely unknown. We found a strikingly interesting phenomenon that cancer cells in triple-negative breast cancer (TNBC) tumors with low FOXF2 expression and lymph node metastasis could form lymphatic vessel-like structures, which were termed as lymphangiogenic mimicry. Our experimental data showed that VEGF-C/VEGFR3 signaling could induce basal-like breast cancer (BLBC) cells to have lymphatic endothelial cells phenotype, and FOXF2 inhibited BLBC lymphatic metastasis. Our previous studies showed that FOXF2 deficiency promotes epithelial-mesenchymal transition (EMT) of BLBC cells. Increasing studies reveal that cancer cells acquire stem cells properties via EMT, and cancer stem cell (CSC) and EMT are essential in the epithelium-endothelium transition (EET) process. Based on the literatures and our experimental results, we propose a hypothesis that FOXF2 deficiency promotes BLBC cells to acquire more stem cells properties so that VEGF-C/VEGFR3 signaling could induce BLBC cells to transdifferentiate to lymphatic endothelium-like cells and form lymphangiogenic mimicry easily. BLBC metastasize to lymph node through lymphangiogenic mimicry. The purposes of this study are to verify the authenticity of lymphangiogenic mimicry, and to investigate the role and mechanism of FOXF2 in inhibiting BLBC lymphangiogenic mimicry.

淋巴道转移是乳腺癌最常见转移途径，乳腺癌淋巴结转移与肿瘤淋巴管生成相关，然而肿瘤淋巴管生成机制尚不完全清楚。我们在FOXF2低表达且发生淋巴结转移的三阴性乳腺癌组织中偶然发现肿瘤细胞构成淋巴管的现象，暂称为淋巴管生成拟态。实验发现基底样乳腺癌细胞VEGF-C/VEGFR3信号通路激活后拥有淋巴管内皮细胞表型，FOXF2抑制基底样乳腺癌淋巴结转移。我们先前文献报道FOXF2缺失能促进基底样乳腺癌细胞上皮间质转化。研究指出肿瘤细胞发生上皮间质转化可获得干细胞特性，具备发生上皮内皮转化的潜能。基于此提出立项假设：FOXF2缺失表达的基底样乳腺癌细胞拥有更强的干细胞特性，VEGF-C/VEGFR3信号通路激活后转分化成类淋巴管内皮细胞，形成淋巴管生成拟态。基底样乳腺癌借助淋巴管生成拟态进行淋巴结转移。本项目旨在证实淋巴管生成拟态的存在，并阐明FOXF2抑制基底样乳腺癌淋巴管生成拟态的作用和机制。

淋巴道转移是乳腺癌主要的转移途径，尤其是晚期基底样乳腺癌（BLBC）患者常发生淋巴结转移，影响患者预后。研究清楚肿瘤淋巴管生成机制和BLBC淋巴结转移机制具有重要意义。我们发现BLBC细胞能够表达淋巴管内皮细胞标志物，形成淋巴管样结构，我们称此现象为淋巴管生成拟态。该发现首次揭示了淋巴管生成拟态作为肿瘤淋巴管生成的一种新机制，为肿瘤细胞淋巴结转移建立通道。VEGF-C/VEGFR3信号通路能诱导BLBC细胞形成淋巴管生成拟态。转录因子FOXF2通过结合VEGFR3基因启动子并抑制其转录，阻断VEGF-C/VEGFR3信号通路，抑制BLBC细胞形成淋巴管生成拟态和淋巴道转移。FOXF2有待成为预测BLBC患者预后的指标及抗淋巴结转移的候选靶点。. 我们证明了在肿瘤微环境中淋巴管内皮细胞通过CXCL12/CXCR4信号通路趋化BLBC细胞，使两种类型细胞在物理距离上拉近。然后淋巴管内皮细胞通过VEGF-C/VEGFR3信号通路驯化BLBC细胞形成淋巴管生成拟态，引导肿瘤细胞进行淋巴道转移。动物实验表明诱导淋巴管生成拟态的凋亡破坏，阻断CXCL12/CXCR4通路破坏淋巴管内皮细胞与BLBC细胞之间的联络，应用VEGF-C/VEGFR3信号通路阻断剂抑制淋巴管生成拟态，这三种策略均能有效阻止BLBC的淋巴结转移，为寻找抗BLBC淋巴结转移的防治方法提供有益线索。

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