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实验性膀胱癌中的淋巴管密度与功能

Lymphatic vessel density and function in experimental bladder cancer.

作者信息

Saban Marcia R, Towner Rheal, Smith Nataliya, Abbott Andrew, Neeman Michal, Davis Carole A, Simpson Cindy, Maier Julie, Mémet Sylvie, Wu Xue-Ru, Saban Ricardo

机构信息

Department of Physiology, College of Medicine, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USA.

出版信息

BMC Cancer. 2007 Nov 29;7:219. doi: 10.1186/1471-2407-7-219.

DOI:10.1186/1471-2407-7-219
PMID:18047671
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2241841/
Abstract

BACKGROUND

The lymphatics form a second circulatory system that drains the extracellular fluid and proteins from the tumor microenvironment, and provides an exclusive environment in which immune cells interact and respond to foreign antigen. Both cancer and inflammation are known to induce lymphangiogenesis. However, little is known about bladder lymphatic vessels and their involvement in cancer formation and progression.

METHODS

A double transgenic mouse model was generated by crossing a bladder cancer-induced transgenic, in which SV40 large T antigen was under the control of uroplakin II promoter, with another transgenic mouse harboring a lacZ reporter gene under the control of an NF-kappaB-responsive promoter (kappaB-lacZ) exhibiting constitutive activity of beta-galactosidase in lymphatic endothelial cells. In this new mouse model (SV40-lacZ), we examined the lymphatic vessel density (LVD) and function (LVF) during bladder cancer progression. LVD was performed in bladder whole mounts and cross-sections by fluorescent immunohistochemistry (IHC) using LYVE-1 antibody. LVF was assessed by real-time in vivo imaging techniques using a contrast agent (biotin-BSA-Gd-DTPA-Cy5.5; Gd-Cy5.5) suitable for both magnetic resonance imaging (MRI) and near infrared fluorescence (NIRF). In addition, IHC of Cy5.5 was used for time-course analysis of co-localization of Gd-Cy5.5 with LYVE-1-positive lymphatics and CD31-positive blood vessels.

RESULTS

SV40-lacZ mice develop bladder cancer and permitted visualization of lymphatics. A significant increase in LVD was found concomitantly with bladder cancer progression. Double labeling of the bladder cross-sections with LYVE-1 and Ki-67 antibodies indicated cancer-induced lymphangiogenesis. MRI detected mouse bladder cancer, as early as 4 months, and permitted to follow tumor sizes during cancer progression. Using Gd-Cy5.5 as a contrast agent for MRI-guided lymphangiography, we determined a possible reduction of lymphatic flow within the tumoral area. In addition, NIRF studies of Gd-Cy5.5 confirmed its temporal distribution between CD31-positive blood vessels and LYVE-1 positive lymphatic vessels.

CONCLUSION

SV40-lacZ mice permit the visualization of lymphatics during bladder cancer progression. Gd-Cy5.5, as a double contrast agent for NIRF and MRI, permits to quantify delivery, transport rates, and volumes of macromolecular fluid flow through the interstitial-lymphatic continuum. Our results open the path for the study of lymphatic activity in vivo and in real time, and support the role of lymphangiogenesis during bladder cancer progression.

摘要

背景

淋巴管形成了第二个循环系统，可从肿瘤微环境中引流细胞外液和蛋白质，并提供一个免疫细胞相互作用并对外来抗原作出反应的独特环境。已知癌症和炎症均可诱导淋巴管生成。然而，关于膀胱淋巴管及其在癌症形成和进展中的作用知之甚少。

方法

通过将一种膀胱癌诱导转基因小鼠（其中SV40大T抗原受uroplakin II启动子控制）与另一种转基因小鼠杂交，构建了一种双转基因小鼠模型，该转基因小鼠携带一个在NF-κB反应性启动子（κB-lacZ）控制下的lacZ报告基因，在淋巴管内皮细胞中表现出β-半乳糖苷酶的组成型活性。在这个新的小鼠模型（SV40-lacZ）中，我们研究了膀胱癌进展过程中的淋巴管密度（LVD）和功能（LVF）。通过使用LYVE-1抗体的荧光免疫组织化学（IHC）对膀胱全层和横截面进行LVD检测。使用适用于磁共振成像（MRI）和近红外荧光（NIRF）的造影剂（生物素-BSA-Gd-DTPA-Cy5.5；Gd-Cy5.5），通过实时体内成像技术评估LVF。此外，使用Cy5.5的IHC对Gd-Cy5.5与LYVE-1阳性淋巴管和CD31阳性血管的共定位进行时间进程分析。

结果

SV40-lacZ小鼠发生膀胱癌并可观察到淋巴管。发现LVD随着膀胱癌进展而显著增加。用LYVE-1和Ki-67抗体对膀胱横截面进行双重标记表明存在癌症诱导的淋巴管生成。MRI早在4个月时就检测到小鼠膀胱癌，并可在癌症进展过程中追踪肿瘤大小。使用Gd-Cy5.5作为MRI引导淋巴管造影的造影剂，我们确定肿瘤区域内淋巴管血流可能减少。此外，对Gd-Cy5.5的NIRF研究证实了其在CD31阳性血管和LYVE-1阳性淋巴管之间的时间分布。

结论

SV40-lacZ小鼠可在膀胱癌进展过程中观察到淋巴管。Gd-Cy5.5作为NIRF和MRI的双重造影剂，可对通过间质-淋巴连续体的大分子流体流动的输送、运输速率和体积进行量化。我们的结果为体内实时研究淋巴活动开辟了道路，并支持淋巴管生成在膀胱癌进展中的作用。

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