Liu Pengpeng, Zhang Rui, Han Lei, Zhang Xiao, Ye Yingnan, Yu Wenwen, Ren Xiubao, Zhang Weijia, Yu Jinpu
Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Ann Transl Med. 2022 Jan;10(2):39. doi: 10.21037/atm-21-4865.
Tumor lymphatic metastasis is mostly dependent on lymphangiogenesis, which was less studied compared to angiogenesis and the molecular mechanisms involved remained unclear.
We analyzed the mRNA expression profiles of 937 primary lung squamous cell carcinoma (LUSC) samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to explore the genes related to lymphatic metastasis in LUSC. We focused on vasohibin 2 (VASH2) and investigated its biological functions in LUSC proliferation, apoptosis, migration, invasion, as well as lymphangiogenesis capacity by forced over-expressing VASH2 in LUSC cell line H520 and . We also evaluated the anti-tumor efficacy of specific anti-VASH2 antibody in LUSC xenograft-bearing mice models.
Vasohibin2 (VASH2) was filtered out as a significant predictive factor of poor prognosis and lymphatic metastasis in LUSC patients both in public datasets and an independent Chinese LUSC cohort. VASH2 promoted the proliferation and invasion of LUSC cells in vitro and vivo. Forced over-expression of VASH2 in LUSC cells promoted the amplification and tube formation capacity of human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) via up-regulating vascular endothelial growth factor-D (VEGF-D), which could be reversed via Snail inhibition. Furthermore, blocking VASH2/VEGF-D signaling using specific antibodies dramatically inhibited tumor growth in mice by interfering with the proliferation of cancer cells and lymphangiogenesis in tumor tissues.
In conclusion, VASH2 facilitated lymphangiogenesis and tumor growth in a Snail-dependent manner and might serve as a novel biomarker for early diagnosis and prognosis prediction, as well as a potential therapeutic target in LUSC.
肿瘤淋巴转移大多依赖于淋巴管生成，与血管生成相比，对其研究较少，涉及的分子机制仍不清楚。
我们分析了来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的937例原发性肺鳞状细胞癌（LUSC）样本的mRNA表达谱，以探索LUSC中与淋巴转移相关的基因。我们聚焦于血管抑制素2（VASH2），并通过在LUSC细胞系H520中强制过表达VASH2来研究其在LUSC增殖、凋亡、迁移、侵袭以及淋巴管生成能力方面的生物学功能。我们还评估了特异性抗VASH2抗体在携带LUSC异种移植瘤小鼠模型中的抗肿瘤疗效。
在公共数据集和一个独立的中国LUSC队列中，血管抑制素2（VASH2）被筛选为LUSC患者预后不良和淋巴转移的重要预测因子。VASH2在体外和体内均促进LUSC细胞的增殖和侵袭。在LUSC细胞中强制过表达VASH2通过上调血管内皮生长因子-D（VEGF-D）促进人脐静脉内皮细胞（HUVECs）和人淋巴管内皮细胞（HLECs）的扩增和管腔形成能力，而这种作用可通过抑制Snail来逆转。此外，使用特异性抗体阻断VASH2/VEGF-D信号通路可通过干扰癌细胞增殖和肿瘤组织中的淋巴管生成显著抑制小鼠肿瘤生长。
总之，VASH2以Snail依赖的方式促进淋巴管生成和肿瘤生长，可能作为LUSC早期诊断和预后预测的新型生物标志物以及潜在的治疗靶点。
