Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15894-9. doi: 10.1073/pnas.1208324109. Epub 2012 Sep 11.
Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2-induced lymphangiogenesis. Intriguingly, the VEGFR-3-mediated signaling was required for the lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. Consequently, a VEGFR-3-specific neutralizing antibody markedly inhibited FGF-2-induced lymphangiogenesis. Thus, the VEGFR-3-induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2-stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2- and VEGF-C-induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.
各种淋巴生成因子在促进淋巴管生成和淋巴转移中的相互作用仍知之甚少。在这里，我们表明，两种淋巴生成因子 FGF-2 和 VEGF-C 协同促进肿瘤微环境中的血管生成和淋巴管生成，导致广泛的肺和淋巴结转移。在小鼠角膜中共植入这两种因子可导致血管生成和淋巴管生成的相加效应。在分子水平上，我们表明，在淋巴管内皮细胞中表达的 FGFR-1 是一种关键受体，介导 FGF-2 诱导的淋巴管生成。有趣的是，VEGFR-3 介导的信号通路对于 FGF-2 和 VEGF-C 诱导的淋巴管生成中的淋巴管尖端细胞形成都是必需的。因此，一种 VEGFR-3 特异性中和抗体显著抑制了 FGF-2 诱导的淋巴管生成。因此，VEGFR-3 诱导的淋巴管内皮细胞尖端细胞形成是 FGF-2 刺激淋巴管生成的前提。在肿瘤微环境中，FGF-2 和 VEGF-C 之间的相互作用协同刺激肿瘤生长、血管生成、肿瘤内淋巴管生成和转移。因此，干预和靶向 FGF-2 和 VEGF-C 诱导的血管生成和淋巴管生成协同作用可能是癌症治疗和预防转移的重要方法。
