Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer.
Cancer-Associated Fibroblasts
/ metabolism
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Cells, Cultured
Coculture Techniques
Colonic Neoplasms
/ blood supply
Culture Media, Conditioned
/ pharmacology
Endothelial Cells
/ drug effects
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Neovascularization, Pathologic
/ chemically induced
Tumor Microenvironment
/ physiology
Wnt2 Protein
/ metabolism
3D co-culture
Angiogenesis
Colorectal cancer
Heterotypic cell–cell interactions
Tumor stroma
WNT2
Journal
Angiogenesis
ISSN: 1573-7209
Titre abrégé: Angiogenesis
Pays: Germany
ID NLM: 9814575
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
10
07
2019
accepted:
09
10
2019
revised:
26
09
2019
pubmed:
2
11
2019
medline:
14
1
2021
entrez:
1
11
2019
Statut:
ppublish
Résumé
WNT2 acts as a pro-angiogenic factor in placental vascularization and increases angiogenesis in liver sinusoidal endothelial cells (ECs) and other ECs. Increased WNT2 expression is detectable in many carcinomas and participates in tumor progression. In human colorectal cancer (CRC), WNT2 is selectively elevated in cancer-associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer, angiogenesis was not addressed so far. We demonstrate that WNT2 enhances EC migration/invasion, while it induces canonical WNT signaling in a small subset of cells. Knockdown of WNT2 in CAFs significantly reduced angiogenesis in a physiologically relevant assay, which allows precise assessment of key angiogenic properties. In line with these results, expression of WNT2 in otherwise WNT2-devoid skin fibroblasts led to increased angiogenesis. In CRC xenografts, WNT2 overexpression resulted in enhanced vessel density and tumor volume. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs by mass spectrometry and cytokine arrays revealed that proteins associated with pro-angiogenic functions are elevated by WNT2. These included extracellular matrix molecules, ANG-2, IL-6, G-CSF, and PGF. The latter three increased angiogenesis. Thus, stromal-derived WNT2 elevates angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.
Identifiants
pubmed: 31667643
doi: 10.1007/s10456-019-09688-8
pii: 10.1007/s10456-019-09688-8
pmc: PMC7160098
doi:
Substances chimiques
Culture Media, Conditioned
0
WNT2 protein, human
0
Wnt2 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
159-177Subventions
Organisme : Austrian Science Fund
ID : P29222-B28
Pays : International
Organisme : Austrian Science Fund
ID : SFB F4707 and SFB-F06105
Pays : International
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