Cancer Biology Division, KIIT School of Biotechnology, Kalinga Institute of Industrial Technology, Campus-11, Patia, Bhubaneswar, Odisha 751024, India.
Department of Surgical Oncology, Acharya Harihar Regional Cancer Centre, Cuttack, Odisha 753007, India.
Vascul Pharmacol. 2021 Oct;140:106865. doi: 10.1016/j.vph.2021.106865. Epub 2021 May 1.
Tumor-induced lymphangiogenesis promotes tumor progression by generating new lymphatic vessels that helps in tumor dissemination to regional lymph nodes and distant sites. Recently, the role of Nectin-4 in cancer metastasis and angiogenesis has been studied, but its role in lymphangiogenesis is unknown. Here, we systematically delineated the role of Nectin-4 in lymphangiogenesis and its regulation in invasive duct carcinoma (IDC). Nectin-4 expression positively correlated with occurrence risk factors associated with breast cancer (alcohol, smoke, lifestyle habit, etc), CXCR4 expression, and LYVE-1-lymphatic vessel density (LVD). LVD was significantly higher in axillary lymph node (ALN) than primary tumor. Depleting Nectin-4, VEGF-C or both attenuated the important lymphangiogenic marker LYVE-1 expression, tube formation, and migration of ALN derived primary cells. Nectin-4 stimulated the expressions of CXCR4 and CXCL12 under hypoxic conditions in ALN derived primary cells. Further, Nectin-4 augmented expressions of lymphatic metastatic markers (e.g. eNOS, TGF-β, CD-105) and MMPs. Induced expressions of Nectin-4 along with other representative metastatic markers were noted in lymph and blood circulating tumor cells (LCTCs and BCTCs) of local and distant metastatic samples. Thus, Nectin-4 displayed a predominant role in promoting tumor-induced lymphangiogenesis and lymphatic metastasis by modulating CXCR4/CXCL12-LYVE-1- axis.
肿瘤诱导的淋巴管生成通过生成新的淋巴管促进肿瘤进展，有助于肿瘤向区域淋巴结和远处部位扩散。最近，研究了 Nectin-4 在癌症转移和血管生成中的作用，但它在淋巴管生成中的作用尚不清楚。在这里，我们系统地描述了 Nectin-4 在淋巴管生成中的作用及其在浸润性导管癌 (IDC) 中的调节作用。Nectin-4 的表达与乳腺癌的发生风险因素（酒精、吸烟、生活习惯等）、CXCR4 表达和 LYVE-1-淋巴管密度 (LVD) 呈正相关。腋窝淋巴结 (ALN) 中的 LVD 明显高于原发性肿瘤。敲低 Nectin-4、VEGF-C 或两者都可减弱重要的淋巴管生成标志物 LYVE-1 的表达、管形成和 ALN 衍生的原代细胞的迁移。Nectin-4 在 ALN 衍生的原代细胞中在缺氧条件下刺激 CXCR4 和 CXCL12 的表达。此外，Nectin-4 增强了淋巴转移标志物（如 eNOS、TGF-β、CD-105）和 MMPs 的表达。在局部和远处转移样本的淋巴和血液循环肿瘤细胞 (LCTC 和 BCTC) 中观察到 Nectin-4 与其他代表性转移标志物的诱导表达。因此，Nectin-4 通过调节 CXCR4/CXCL12-LYVE-1-轴，在促进肿瘤诱导的淋巴管生成和淋巴转移方面发挥主要作用。
