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Cancer-associated mesothelial cell-derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis.
JCI insight 8:17 (2023)
Ovarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell-lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Using omental samples from patients with high-grade serous OvCa and mouse models with Wt1-driven GFP-expressing mesothelial cells, we validated the intratumoral localization of mesothelial cells during human and mouse OvCa omental metastasis. Removing mesothelial cells ex vivo from human and mouse omenta or in vivo using diphtheria toxin mediated ablation in Msln-Cre mice, significantly inhibited OvCa cell adhesion and colonization. Human ascites induced angiopoietin-like 4 (ANGPTL4) and stanniocalcin 1 (STC1) expression and secretion by mesothelial cells. Inhibition of STC1 or ANGPTL4 via RNAi, obstructed OvCa cell-induced mesothelial cell to mesenchymal transition while inhibition of ANGPTL4 alone obstructed OvCa cell-induced mesothelial cell migration and glycolysis. Inhibition of mesothelial cell ANGPTL4 secretion via RNAi prevented mesothelial cell induced monocyte migration, endothelial cell vessel formation and OvCa cell adhesion, migration, and proliferation. In contrast, inhibition of mesothelial cell STC1 secretion via RNAi prevented mesothelial cell induced endothelial cell vessel formation and OvCa cell adhesion, migration, proliferation, and invasion. Additionally, blocking ANPTL4 function with antibodies reduced the ex vivo colonization of three different OvCa cell lines on human omental tissue explants and in vivo colonization of ID8p53-/-Brca2-/- cells on mouse omenta. These findings indicate that mesothelial cells are important to the initial stages of OvCa metastasis, and that the crosstalk between mesothelial cells and the tumor microenvironment, promotes OvCa metastasis through the secretion of ANGPTL4.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cancer ; Cell Biology ; Mouse Models ; Obstetrics/gynecology ; Oncology; Angiopoietin-like 4; Stanniocalcin 1; Fibroblasts; Expression; Immunotherapy; Prognosis; Biomarker; Invasion
Language
english
Publication Year
2023
HGF-reported in Year
2023
ISSN (print) / ISBN
2379-3708
e-ISSN
2379-3708
Journal
JCI insight
Quellenangaben
Volume: 8,
Issue: 6,
Article Number: 17
Publisher
Clarivate
Publishing Place
Ann Arbor, Michigan
Reviewing status
Peer reviewed
Institute(s)
Institute of Regenerative Biology and Medicine (IRBM)
POF-Topic(s)
30202 - Environmental Health
Research field(s)
Lung Research
PSP Element(s)
G-509400-001
Grants
Cancer Center Support
NIH
Liz Tilberis Early Career Investigator Grant from the Ovarian Cancer Research Alliance
NIH
Liz Tilberis Early Career Investigator Grant from the Ovarian Cancer Research Alliance
WOS ID
000957352400001
Scopus ID
85150752332
PubMed ID
36795484
Erfassungsdatum
2023-02-23