Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor
Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor
复制标题
DOI：
10.1158/0008-5472.can-05-0408
复制
发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Jooss, K
中科院分区：
文献类型：
--
作者：
Lin, JM;Lalani, AS;Jooss, K
在许多类型的癌症中，区域淋巴结转移的存在是患者存活率差的强指标。最近研究表明，淋巴管生成生长因子、血管内皮生长因子-C（VEGF-C）及其受体VEGF受体-3（VEGFR 3）可能在促进局部淋巴结转移中起关键作用。在这项研究中，人前列腺和黑色素瘤肿瘤模型，优先转移到淋巴结后，s.c.通过体内选择从淋巴结转移建立肿瘤细胞植入。从淋巴结转移建立的黑素瘤肿瘤细胞亚系表达比亲本肿瘤细胞更高量的VEGF-C。当在肿瘤植入前开始治疗时，用通过重组腺相关病毒载体表达的可溶性VEGFR 3诱饵受体sVEGFR 3-Fc抑制肿瘤衍生的VEGF-C，有效地阻断肿瘤相关的淋巴管生成和肿瘤转移到淋巴结。此外，有效阻断淋巴结转移所需的sVEGFR 3-Fc血清水平严格依赖于原发性肿瘤产生的VEGF-C水平。重组腺相关病毒介导的sVEGFR 3-Fc基因转移可能代表一种可行的治疗策略，用于阻断淋巴转移。
The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival in many types of cancer. It has recently been shown that the lymphangiogenic growth factor, vascular endothelial growth factor-C (VEGF-C), and its receptor, VEGF receptor-3 (VEGFR3), may play a pivotal role in the promotion of metastasis to regional lymph nodes. In this study, human prostate and melanoma tumor models that preferentially metastasize to the lymph nodes following s.c. tumor cell implantation were established from lymph node metastases via in vivo selection. Melanoma tumor cell sublines established from lymph node metastasis express higher amounts of VEGF-C than the parental tumor cells. The inhibition of tumor-derived VEGF-C with a soluble VEGFR3 decoy receptor, sVEGFR3-Fc, expressed via a recombinant adeno-associated viral vector, potently blocks tumor-associated lymphangiogenesis and tumor metastasis to the lymph nodes, when the treatment was initiated before the tumor implantation. In addition, sVEGFR3-Fc serum levels required for efficient blockade of lymph node metastases are strictly dependent on the VEGF-C levels generated by the primary tumor. Recombinant adeno-associated virus-mediated gene transfer of sVEGFR3-Fc may represent a feasible therapeutic strategy for blockade of lymphogenous metastasis.