Lymphatic vessel remodeling and invasion in pancreatic cancer progression
Journal
EBioMedicine
Journal Volume
47
Pages
98-113
Date Issued
2019
Author(s)
Shen C.-N.
Goh K.-S.
Huang C.-R.
Chiang T.-C.
Peng S.-J.
Chien H.-J.
Chung M.-H.
Chou Y.-H.
Hsieh C.-C.
Kulkarni S.
Pasricha P.J.
Tang S.-C.
Abstract
Background: 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. Methods: 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. Findings: 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-KrasG12D and elastase-CreER;LSL-KrasG12D;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. Interpretation: 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). ? 2019
SDGs
Other Subjects
cre recombinase; elastase; K ras protein; biological marker; aged; animal cell; animal experiment; animal model; animal tissue; Article; blood vessel reactivity; cancer growth; cancer staging; carcinogenesis; comparative study; controlled study; female; human; human tissue; lymphangiogenesis; lymphatic vessel remodeling; major clinical study; male; mouse model; nonhuman; pancreas adenocarcinoma; pancreas adenoma; pancreatectomy; priority journal; quantitative analysis; scanning electron microscopy; three dimensional imaging; tumor invasion; tumor microenvironment; tumor vascularization; vascular remodeling; animal; disease exacerbation; disease model; fluorescent antibody technique; lymph node; lymph vessel; metabolism; mouse; neovascularization (pathology); pancreas tumor; pathology; xenograft; Animals; Biomarkers; Disease Models, Animal; Disease Progression; Fluorescent Antibody Technique; Heterografts; Humans; Lymph Nodes; Lymphatic Vessels; Mice; Neovascularization, Pathologic; Pancreatic Neoplasms; Tumor Microenvironment; Vascular Remodeling
Publisher
Elsevier B.V.
Type
journal article