Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis.
Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis.
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DOI：
10.1158/0008-5472.can-08-1488
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Burton JB;Priceman SJ;Sung JL;Brakenhielm E;An DS;Pytowski B;Alitalo K;Wu L
淋巴结受累提示前列腺癌患者预后不良。我们的研究小组，沿着其他研究小组，在小鼠模型中已经证明，最初的肿瘤细胞通过淋巴结扩散到局部淋巴结也会促进全身转移。本研究的目的是研究靶向血管生成或淋巴管生成轴的抑制性治疗在抑制皮下和原位前列腺肿瘤异种移植物的区域淋巴结和全身转移中的疗效。雄激素依赖性和更具侵略性的雄激素非依赖性前列腺肿瘤在我们的调查中使用。有趣的是，我们观察到，与皮下移植肿瘤相比，在血管丰富的前列腺微环境中传播的阈值较低。血管内皮生长因子-C（VEGF-C）配体陷阱（sVEGFR-3）和针对VEGFR-3的抗体（mF 4 - 31 C1）均显著减少肿瘤淋巴管生成和向区域淋巴结和远端重要器官的转移，而不影响肿瘤生长。相反，血管生成阻断短发夹RNA对VEGF或抗VEGFR-2抗体（DC 101）减少肿瘤血管密度，显着延迟肿瘤生长，并减少全身转移，但它是无效的，在减少淋巴管生成或淋巴结转移。总的来说，这些数据阐明了血管治疗在前列腺肿瘤生长和转移中的效用，特别是在前列腺微环境的背景下。我们的研究结果强调了淋巴管生成治疗在控制区域淋巴结和全身转移中的重要性。
Lymph node involvement denotes a poor outcome for patients with prostate cancer. Our group, along with others, has shown that initial tumor cell dissemination to regional lymph nodes via lymphatics also promotes systemic metastasis in mouse models. The aim of this study was to investigate the efficacy of suppressive therapies targeting either the angiogenic or lymphangiogenic axis in inhibiting regional lymph node and systemic metastasis in subcutaneous and orthotopic prostate tumor xenografts. Both androgen-dependent and more aggressive androgen-independent prostate tumors were used in our investigations. Interestingly, we observed that the threshold for dissemination is lower in the vascular-rich prostatic microenvironment compared with subcutaneously grafted tumors. Both vascular endothelial growth factor-C (VEGF-C) ligand trap (sVEGFR-3) and antibody directed against VEGFR-3 (mF4-31C1) significantly reduced tumor lymphangiogenesis and metastasis to regional lymph nodes and distal vital organs without influencing tumor growth. Conversely, angiogenic blockade by short hairpin RNA against VEGF or anti–VEGFR-2 antibody (DC101) reduced tumor blood vessel density, significantly delayed tumor growth, and reduced systemic metastasis, although it was ineffective in reducing lymphangiogenesis or nodal metastasis. Collectively, these data clarify the utility of vascular therapeutics in prostate tumor growth and metastasis, particularly in the context of the prostate microenvironment. Our findings highlight the importance of lymphangiogenic therapies in the control of regional lymph node and systemic metastasis.