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Angiogenesis
Published in: Angiogenesis 2/2020

Open Access 01-05-2020 | Colorectal Cancer | Original Paper

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer

Authors: Daniela Unterleuthner, Patrick Neuhold, Katharina Schwarz, Lukas Janker, Benjamin Neuditschko, Harini Nivarthi, Ilija Crncec, Nina Kramer, Christine Unger, Markus Hengstschläger, Robert Eferl, Richard Moriggl, Wolfgang Sommergruber, Christopher Gerner, Helmut Dolznig

Published in: Angiogenesis | Issue 2/2020

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Abstract

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.
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Metadata
Title
Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer
Authors
Daniela Unterleuthner
Patrick Neuhold
Katharina Schwarz
Lukas Janker
Benjamin Neuditschko
Harini Nivarthi
Ilija Crncec
Nina Kramer
Christine Unger
Markus Hengstschläger
Robert Eferl
Richard Moriggl
Wolfgang Sommergruber
Christopher Gerner
Helmut Dolznig
Publication date
01-05-2020
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 2/2020
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-019-09688-8

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