Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: Therapeutic implications.
Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: Therapeutic implications.
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DOI：
10.1158/0008-5472.can-06-1392
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Hoshida, Tohru;Isaka, Naohide;Jain, Rakesh K.
临床前和临床研究表明，血管内皮生长因子（VEGF）-C在肿瘤中的表达与淋巴结转移的发生率呈正相关。然而，VEGF-C如何调节肿瘤细胞从原发性肿瘤到引流淋巴结的转运中的各个步骤还知之甚少。在这里，我们使用引流淋巴管和淋巴结的活体显微镜对小鼠耳尖中生长的肿瘤中的这些步骤进行成像和量化，这些淋巴管和淋巴结接收自发脱落的肿瘤细胞。我们发现，VEGF-C在癌细胞中的过度表达诱导了瘤周淋巴管的增生，并使耳根淋巴管的体积流速增加了40%。淋巴流速和瘤周淋巴表面积的增加提高了肿瘤细胞递送到淋巴结的速率，导致淋巴结中癌细胞积累增加200倍，淋巴结转移增加4倍。在我们的模型中，VEGF-C过表达并没有赋予癌细胞任何存活或生长优势。我们还表明，抗VEGF受体（VEGFR）-3抗体减少淋巴增生和肿瘤细胞向引流淋巴结的递送，导致淋巴结转移减少。然而，这种治疗无法阻止已经接种在淋巴结中的肿瘤细胞的生长。总的来说，我们的结果表明，VEGF-C通过增加癌细胞向淋巴结的递送而促进淋巴转移，并且针对VEGF-C/VEGFR-3信号传导的疗法靶向淋巴转移的初始步骤。（Cancer Res 2006; 66（16）：8065-75）
Preclinical and clinical studies positively correlate the expression of vascular endothelial growth factor (VEGF)-C in tumors and the incidence of lymph node metastases. However, how VEGF-C regulates individual steps in the transport of tumor cells from the primary tumor to the draining lymph nodes is poorly understood. Here, we image and quantify these steps in tumors growing in the tip of the mouse ear using intravital microscopy of the draining lymphatic vessels and lymph node, which receives spontaneously shed tumor cells. We show that VEGF-C overexpression in cancer cells induces hyperplasia in peritumor lymphatic vessels and increases the volumetric flow rate in lymphatics at the base of the ear by 40%. The increases in lymph flow rate and peritumor lymphatic surface area enhance the rate of tumor cell delivery to lymph nodes, leading to a 200-fold increase in cancer cell accumulation in the lymph node and a 4-fold increase in lymph node metastasis. In our model, VEGF-C overexpression does not confer any survival or growth advantage on cancer cells. We also show that an anti-VEGF receptor (VEGFR)-3 antibody reduces both lymphatic hyperplasia and the delivery of tumor cells to the draining lymph node, leading to a reduction in lymph node metastasis. However, this treatment is unable to prevent the growth of tumor cells already seeded in lymph nodes. Collectively, our results indicate that VEGF-C facilitates lymphatic metastasis by increasing the delivery of cancer cells to lymph nodes and therapies directed against VEGF-C/VEGFR-3 signaling target the initial steps of lymphatic metastasis. (Cancer Res 2006; 66(16): 8065-75)