Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3.
Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3.
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DOI：
10.1186/bcr2903
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发表时间：
2011-06-21
期刊：
影响因子：
--
通讯作者：
Koizumi F
中科院分区：
文献类型：
--
作者：
Kodera Y;Katanasaka Y;Kitamura Y;Tsuda H;Nishio K;Tamura T;Koizumi F
肿瘤转移是癌症患者的常见事件，也是导致其死亡的主要原因。淋巴管生成是指新的淋巴管的形成，被认为与转移的发展有关。舒尼替尼是一种多激酶抑制剂，可阻断受体酪氨酸激酶活性，包括血管内皮生长因子受体（VEGFRs）。虽然舒尼替尼是临床上可用的血管生成抑制剂，但其对淋巴管生成和淋巴结转移的影响尚不清楚。本研究的目的是研究舒尼替尼对血管内皮生长因子受体3 （VEGFR-3）和相关事件——淋巴管生成的影响。在经舒尼替尼治疗的淋巴内皮细胞（LECs）中检测舒尼替尼对VEGFR-2/3和其他信号分子磷酸化程度的影响；vegf诱导的LEC生长、迁移和管形成也被检测。在体内研究中，将表达荧光素酶的乳腺癌细胞移植到小鼠乳腺脂肪垫中；舒尼替尼联合抗vegfr -2抗体治疗后，测定微血管和淋巴管密度。首先，在人类LECs中，舒尼替尼阻断了VEGF-C或VEGF-D诱导的VEGFR-2和VEGFR-3磷酸化，并消除了下游分子细胞外信号调节激酶1/2 （ERK1/2）和Akt的激活。舒尼替尼降低VEGF-C/D诱导的细胞增殖活性，阻止VEGF-C诱导的内皮细胞迁移和成管；然而，抗vegfr2治疗仅对LECs的生长和功能有部分影响。我们使用表达荧光素酶的乳腺癌细胞系作为转移性癌症模型。舒尼替尼治疗（40 mg/kg/天）可抑制小鼠乳腺脂肪垫原发肿瘤的生长，并显著减少肿瘤内的血管和淋巴管数量。此外，通过生物发光成像检测，腋窝淋巴结转移的发展明显受到抑制。舒尼替尼的这种作用比抗小鼠VEGFR-2抗体DC101更有效。结果表明，舒尼替尼可能通过抑制VEGFR-3（尤其重要）来抑制淋巴管生成和淋巴结转移，从而对乳腺癌的治疗有益。
Metastasis is a common event and the main cause of death in cancer patients. Lymphangiogenesis refers to the formation of new lymphatic vessels and is thought to be involved in the development of metastasis. Sunitinib is a multi-kinase inhibitor that blocks receptor tyrosine kinase activity, including that of vascular endothelial growth factor receptors (VEGFRs). Although sunitinib is a clinically available angiogenesis inhibitor, its effects on lymphangiogenesis and lymph node metastasis remain unclear. The purpose of this study was to investigate the effects of sunitinib on vascular endothelial growth factor receptor 3 (VEGFR-3) and a related event, lymphangiogenesis. The effects of sunitinib on the degree of phosphorylation of VEGFR-2/3 and other signaling molecules was examined in lymphatic endothelial cells (LECs) treated with the drug; VEGF-induced LEC growth, migration, and tube formation were also examined. For the in vivo study, luciferase-expressing breast cancer cells were transplanted into mammary fat pads of mice; the microvessel and lymphatic vessel density was then measured after treatment with sunitinib and anti-VEGFR-2 antibody. First, in human LECs, sunitinib blocked both VEGFR-2 and VEGFR-3 phosphorylation induced by VEGF-C or VEGF-D, and abrogated the activation of the downstream molecules extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. Furthermore, sunitinib attenuated the cell-proliferation activity induced by VEGF-C/D and prevented VEGF-C-induced migration and tube formation of the LECs; however, anti-VEGFR2 treatment shows only a partial effect on the growth and functions of the LECs. We used a breast cancer cell line expressing luciferase as a metastatic cancer model. Sunitinib treatment (40 mg/kg/day) inhibited the growth of the primary tumor transplanted in the mammary fat pad of the mice and significantly reduced the number of blood and lymphatic vessels in the tumor. Furthermore, the development of axillary lymph node metastasis, detected by bioluminescent imaging, was markedly suppressed. This effect of sunitinib was more potent than that of DC101, an anti-mouse VEGFR-2 antibody. The results suggest that sunitinib might be beneficial for the treatment of breast cancer by suppressing lymphangiogenesis and lymph node metastasis, through inhibition, particularly important, of VEGFR-3.
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DOI：
10.1186/bcr1026
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jenkins DE;Hornig YS;Oei Y;Dusich J;Purchio T
通讯作者：
Purchio T
影响因子：
82.9
作者：
Skobe, M;Hawighorst, T;Detmar, M
通讯作者：
Detmar, M
DOI：
10.1093/jnci/94.11.819
发表时间：
2002-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
He, YL;Kozaki, KI;Alitalo, K
通讯作者：
Alitalo, K
影响因子：
11.2
作者：
Heckman, Caroline A.;Holopainen, Tanja;Alitalo, Kari
通讯作者：
Alitalo, Kari
DOI：
10.1073/pnas.242401399
发表时间：
2002-12-10
影响因子：
11.1
作者：
Podgrabinska, S;Braun, P;Skobe, M
通讯作者：
Skobe, M