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

Angiogenesis. 2020 May;23(2):159-177. doi: 10.1007/s10456-019-09688-8. Epub 2019 Oct 30.


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.

Keywords: 3D co-culture; Angiogenesis; Colorectal cancer; Heterotypic cell–cell interactions; Tumor stroma; WNT2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cancer-Associated Fibroblasts / metabolism*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Culture Media, Conditioned / pharmacology
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Neovascularization, Pathologic / chemically induced*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Tumor Microenvironment / physiology
  • Wnt2 Protein / metabolism*
  • Wnt2 Protein / pharmacology*


  • Culture Media, Conditioned
  • WNT2 protein, human
  • Wnt2 Protein