Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
EBioMedicine. 2019 Sep;47:98-113. doi: 10.1016/j.ebiom.2019.08.044. Epub 2019 Sep 5.
The lymphatic system is involved in metastasis in pancreatic cancer progression. In cancer staging, lymphatic spread has been used to assess the invasiveness of tumor cells. However, from the endothelium's perspective, the analysis downplays the peri-lesional activities of lymphatic vessels. This unintended bias is largely due to the lack of 3-dimensional (3-D) tissue information to depict the lesion microstructure and vasculature in a global and integrated fashion.
We targeted the pancreas as the model organ to investigate lymphatic vessel remodeling in cancer lesion progression. Transparent pancreases were prepared by tissue clearing to facilitate deep-tissue, tile-scanning microscopy for 3-D lymphatic network imaging.
In human pancreatic ductal adenocarcinoma, we identify the close association between the pancreatic intraepithelial neoplasia (PanIN) lesions and the lymphatic network. In mouse models of PanIN (elastase-CreER;LSL-Kras and elastase-CreER;LSL-Kras;p53), the 3-D image data reveal the peri-lesional lymphangiogenesis, endothelial invagination, formation of the bridge/valve-like luminal tubules, vasodilation, and luminal invasion. In the orthotopic mouse model of pancreatic cancer, we identify the localized, graft-induced lymphangiogenesis and the peri- and intra-tumoral lymphatic vessel invasion.
The integrated view of duct lesions and vascular remodeling suggests an active role, rather than a passive target, of lymphatic vessels in the metastasis of pancreatic cancer. Our 3-D image data provide insights into the pancreatic cancer microenvironment and establish the technical and morphological foundation for systematic detection and 3-D analysis of lymphatic vessel invasion. FUND: Taiwan Academia Sinica (AS-107-TP-L15 and AS-105-TP-B15), Ministry of Science and Technology (MOST 106-2321-B-001-048, 106-0210-01-15-02, 106-2321-B-002-034, and 106-2314-B-007-004-MY2), and Taiwan National Health Research Institutes (NHRI EX107-10524EI).
淋巴系统参与胰腺癌进展中的转移。在癌症分期中，淋巴扩散已被用于评估肿瘤细胞的侵袭性。然而，从内皮细胞的角度来看，这种分析忽略了淋巴管在病灶周围的活动。这种无意的偏差在很大程度上是由于缺乏 3 维（3-D）组织信息来描绘病变的微观结构和脉管系统的全局和综合方式。
我们以胰腺为模型器官，研究癌症病变进展中淋巴管的重塑。通过组织透明化制备透明胰腺，以促进深层组织、平铺扫描显微镜对 3-D 淋巴管网络成像。
在人类胰腺导管腺癌中，我们发现胰腺上皮内瘤变（PanIN）病变与淋巴管密切相关。在 PanIN 的小鼠模型（弹性蛋白酶-CreER；LSL-Kras 和弹性蛋白酶-CreER；LSL-Kras;p53）中，3-D 图像数据揭示了病灶周围的淋巴管生成、内皮内陷、桥/瓣状管腔形成、血管扩张和管腔侵犯。在胰腺癌细胞的原位小鼠模型中，我们发现了局部的、移植物诱导的淋巴管生成以及肿瘤周围和内部的淋巴管侵犯。
导管病变和血管重塑的综合观点表明，淋巴管在胰腺癌转移中发挥着积极的作用，而不是被动的靶点。我们的 3-D 图像数据提供了对胰腺癌微环境的深入了解，并为系统检测和 3-D 分析淋巴管侵犯奠定了技术和形态学基础。
台湾中央研究院（AS-107-TP-L15 和 AS-105-TP-B15）、科技部（MOST 106-2321-B-001-048、106-0210-01-15-02、106-2321-B-002-034 和 106-2314-B-007-004-MY2）和台湾国家卫生研究院（NHRI EX107-10524EI）。
Zotero 插件
