Lymphotoxin-α promotes tumor angiogenesis in HNSCC by modulating glycolysis in a PFKFB3-dependent manner
Lymphotoxin-α promotes tumor angiogenesis in HNSCC by modulating glycolysis in a PFKFB3-dependent manner
复制标题
淋巴毒素-α 通过以 PFKFB3 依赖性方式调节糖酵解促进 HNSCC 中的肿瘤血管生成
DOI：
10.1002/ijc.32221
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发表时间：
2019-09-01
影响因子：
6.4
通讯作者：
Zhao, Yi-Fang
中科院分区：
文献类型：
--
作者：
Yang, Jie-Gang;Wang, Wei-Ming;Zhao, Yi-Fang
肿瘤血管生成是肿瘤进展的关键，因为新血管提供营养并促进转移。既往研究表明肿瘤相关淋巴细胞（包括B细胞和T细胞）参与肿瘤血管生成和肿瘤进展。本研究旨在探讨活化淋巴细胞分泌的光敏素-α（LT-α）在头颈部鳞状细胞癌（HNSCC）肿瘤血管生成中的作用。HNSCC细胞系Cal 27与原代淋巴细胞的共培养体系显示，肿瘤细胞促进共培养淋巴细胞中LT-α的分泌。体外实验结果进一步证明，LT-α通过增强PFKFB 3介导的糖酵解通量，促进人脐静脉内皮细胞（HUVECs）的增殖、迁移和管腔形成。PFKFB 3的遗传和药理学抑制抑制了HUVECs的增殖和迁移。我们进一步确定LT-α诱导的PFKFB 3表达依赖于TNFR/NF-κ B信号通路。此外，我们证明了PFKFB 3阻断降低了HNSCC异种移植物中CD 31阳性血管的密度。最后，来自人HNSCC组织阵列的结果显示，HNSCC样品中LT-α的表达与微血管密度、淋巴细胞浸润和内皮PFKFB 3表达正相关。结论：浸润淋巴细胞分泌的LT-α通过经典的NF-κ B B途径以PFKFB 3依赖的方式促进内皮细胞的糖酵解，促进内皮细胞的增殖和迁移，这可能是HNSCC血管生成异常的原因之一。我们的研究表明，PFKFB 3阻断是一种有前途的治疗方法，通过靶向肿瘤血管生成的HNSCCs。
Tumor angiogenesis is critical for tumor progression as the new blood vessels supply nutrients and facilitate metastasis. Previous studies indicate tumor associated lymphocytes, including B cells and T cells, contribute to tumor angiogenesis and tumor progression. The present study aims to identify the function of Lymphotoxin-alpha (LT-alpha), which is secreted by the activated lymphocytes, in the tumor angiogenesis of head and neck squamous cell carcinoma (HNSCC). The coculture system between HNSCC cell line Cal27 and primary lymphocytes revealed that tumor cells promoted the LT-alpha secretion in the cocultured lymphocytes. In vitro data further demonstrated that LT-alpha promoted the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) by enhancing the PFKFB3-mediated glycolytic flux. Genetic and pharmacological inhibition of PFKFB3 suppressed the enhanced proliferation and migration of HUVECs. We further identified that LT-alpha induced PFKFB3 expression was dependent on the TNFR/NF-kappa B signaling pathway. In addition, we proved that PFKFB3 blockade decreased the density of CD31 positive blood vessels in HNSCC xenografts. Finally, the results from the human HNSCC tissue array revealed that the expression of LT-alpha in HNSCC samples positively correlated with microvessel density, lymphocytes infiltration and endothelial PFKFB3 expression. In conclusion, infiltrated lymphocyte secreted LT-alpha enhances the glycolysis of ECs in a PFKFB3-dependent manner through the classical NF-kappa B pathway and promotes the proliferation and migration of ECs, which may contribute to the aberrant angiogenesis in HNSCCs. Our study suggests that PFKFB3 blockade is a promising therapeutic approach for HNSCCs by targeting tumor angiogenesis.