Enhancement of pleural dissemination and lymph node metastasis of intrathoracic lung cancer cells by vascular endothelial growth factors (VEGFs)
Enhancement of pleural dissemination and lymph node metastasis of intrathoracic lung cancer cells by vascular endothelial growth factors (VEGFs)
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DOI：
10.1016/j.lungcan.2004.02.021
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发表时间：
2004-09-01
期刊：
影响因子：
5.3
通讯作者：
Kitamura, H
中科院分区：
文献类型：
--
作者：
Ishii, H;Yazawa, T;Kitamura, H
包括肺癌在内的肿瘤中血管内皮生长因子（VEGF）的表达被认为与毛细血管和淋巴管新生的肿瘤发展有关。肿瘤细胞播散至胸膜或区域淋巴结是肺癌患者预后不良的关键因素。为了研究胸腔内浸润性肺癌细胞中表达的VEGF如何参与疾病进展，我们建立了稳定表达VEGF-A-、VEGF-C-、VEGF-D-、VEGF-A和VEGF-C-以及表达VEGF-A和VEGF-D的大细胞肺癌克隆（TKB5/VEGF-A、TKB5/VEGF-C、TKB5/VEGF-D、TKB5/VEGF-A/C和TKB5/VEGF-A/D），将其原位接种至裸鼠右胸腔（i.t.），并评估随后的肺损伤、胸腔积液、胸膜的发展。播散和淋巴结转移。白色，空载体转染组（TKB5/空）和每个转染子（i.t.）之间的培养物或皮下肿瘤细胞生长没有显着差异。模型显示转染子之间显着不同的生物学特性。 TKB5/空接种小鼠经常在胸膜上出现大肿瘤，但没有胸腔积液、播散或淋巴结（LN）转移。相反，VEGF-A促进胸膜血血。胸腔积液（6/14），VEGF-A 和 VEGF-D 经常产生胸膜播散（分别为 11/14 和 9/11）。尽管 VEGF-C 和 VEGF-D 均产生淋巴结转移（分别为 6/10 和 8/11），但转移淋巴结的位置却截然不同。 TKB5/VEGF-C 转移到腋窝淋巴结的同侧。 （右腋窝淋巴结），而 TKB5/VEGF-D 转移至纵隔和左腋窝和/或颈部淋巴结。由于 TKB5/VEGF-A/C 或 TKB5/VEGF-A/D 共转染子显示 VEGF-A 和 VEGF-C 或 VEGF-D 的肿瘤进展模式重叠，因此转移性淋巴结具有丰富的新毛细血管，并且比 TKB5/VEGF-C 或 TKB5/VEGF-D 接种的小鼠的更大。我们的结果清楚地表明，胸腔内肺癌细胞分泌的VEGF-A在产生胸腔积液、播散和毛细血管新生中发挥重要作用，VEGF-C参与LN转移，VEGF-D参与胸膜播散和LN转移。然而，VEGF-C 促进淋巴结转移的机制很可能与 VEGF-D 不同。调节胸内肺癌细胞中 VEGF 的表达可能是抑制肿瘤发展和改善患者预后的有效治疗方法。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
The expression of vascular endothelial growth factors (VEGFs) in tumors including lung cancer is considered to be associated with tumor development via capillary and lymph vessel neogenesis. Dissemination of the tumor cells to the pleura or regional lymph nodes is a critical poor prognostic factor for lung cancer patients. To investigate how VEGFs expressed in the intrathoracic infiltrating lung cancer cells participate in disease progression, we established stably VEGF-A-, VEGF-C-, VEGF-D-, VEGF-A and VEGF-C-, and VEGF-A and VEGF-D-expressing large cell lung cancer clones (TKB5/VEGF-A, TKB5/VEGF-C, TKB5/VEGF-D, TKB5/VEGF-A/C, and TKB5/VEGF-A/D), orthotopically inoculated these into the right thoracic cavity (i.t.) of nude mice, and evaluated the subsequent development of lung lesion, pleural effusion, pleural. dissemination, and lymph node metastasis. White there were no significant differences either in culture or in subcutaneous tumor cell growth between the empty vector-transfected group (TKB5/empty) and each transfectant, the i.t. model demonstrated significantly different biological properties between the transfectants. TKB5/empty-inoculated mice frequently developed a large tumor on the pleura without pleural effusion, dissemination, or lymph node (LN) metastasis. In contrast, VEGF-A promoted a bloody pleural. effusion (6/14), and VEGF-A and VEGF-D frequently generated pleural dissemination (11/14 and 9/11, respectively). Although both VEGF-C and VEGF-D generated LN metastasis (6/10 and 8/11, respectively), the locations of the metastasized LNs were quite different. TKB5/VEGF-C metastasized on the same side of axillary LNs as i.t. (right axillary LNs), whereas TKB5/VEGF-D metastasized to the mediastinal and left axillary and/or cervical LNs. Since the TKB5/VEGF-A/C or TKB5/VEGF-A/D co-transfectants revealed overlapping tumor progression patterns of VEGF-A and VEGF-C or VEGF-D, the metastatic LNs had abundant new capillaries and were larger than those of TKB5/VEGF-C or TKB5/VEGF-D-inoculated mice. Our results clearly demonstrate that VEGF-A secreted from intrathoracic lung cancer cells plays important roles in producing pleural effusion, dissemination, and capillary neogenesis, that VEGF-C is involved in LN metastasis, and VEGF-D in pleural dissemination and LN metastasis. It is most likely, however, that the mechanisms by which VEGF-C promotes LN metastasis are different from those of VEGF-D. The regulation of the expression of VEGFs in intrathoracic lung cancer cells might be a useful therapeutic approach to inhibiting tumor development and improving patient prognosis. (C) 2004 Elsevier Ireland Ltd. All rights reserved.