The WNT5A Agonist Foxy5 Reduces the Number of Colonic Cancer Stem Cells in a Xenograft Mouse Model of Human Colonic Cancer

Janina Osman; Kishan Bellamkonda; Qing Liu; Tommy Andersson; Anita Sjölander

doi:10.21873/anticanres.13278

The WNT5A Agonist Foxy5 Reduces the Number of Colonic Cancer Stem Cells in a Xenograft Mouse Model of Human Colonic Cancer

Anticancer Res. 2019 Apr;39(4):1719-1728. doi: 10.21873/anticanres.13278.

Authors

Janina Osman¹, Kishan Bellamkonda¹, Qing Liu¹, Tommy Andersson¹, Anita Sjölander²

Affiliations

¹ Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden.
² Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden [email protected].

PMID: 30952711
DOI: 10.21873/anticanres.13278

Abstract

Background: The wingless-type mammary tumour virus integration site 5A (WNT5A) agonist Foxy5 was shown in vitro to affect intracellular signalling implicated in the regulation of colonic cancer stem cells (CSCs).

Materials and methods: In order to study whether Foxy5 can modulate CSCs, either HT-29 or Caco-2 human colonic cancer cells, both lacking endogenous WNT5A expression, were inoculated subcutaneously into nude mice.

Results: Foxy5 reduced the expression of the stem-cell marker aldehyde dehydrogenase and, interestingly, the specific colon CSC marker double cortin-like kinase 1. Foxy5 also reduced active β-catenin and the expression of its downstream target Achaete Scute complex homolog 2, a CSC-preserving transcription factor. Foxy5 also reduced cyclo-oxygenase 2 expression, responsible for the formation of the CSC-promoting prostaglandin E₂ (PGE₂), but increased that of 15-hydroxyprostaglandin dehydrogenase expression, a PGE₂-degrading enzyme. Accordingly, Foxy5 impairs both β-catenin and PGE₂ signalling, both of which have been implicated in promoting the niche of colonic CSCs.

Conclusion: Our data suggest that Foxy5 can complement the traditional adjuvant chemotherapeutic treatment to which CSCs are resistant.

Keywords: Foxy5 peptide; WNT5A; cancer stem cells; tumour cell signalling.

MeSH terms

Aldehyde Dehydrogenase / genetics
Aldehyde Dehydrogenase / metabolism
Aldehyde Dehydrogenase 1 Family
Animals
Antineoplastic Agents / pharmacology*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Caco-2 Cells
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Cyclooxygenase 2 / metabolism
Dinoprostone / metabolism
Doublecortin-Like Kinases
Female
HT29 Cells
Humans
Hydroxyprostaglandin Dehydrogenases / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Mice, Inbred BALB C
Mice, Nude
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Oligopeptides / pharmacology*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Retinal Dehydrogenase
Tumor Burden / drug effects
Tumor Microenvironment
Wnt Signaling Pathway / drug effects
Wnt-5a Protein / agonists*
Wnt-5a Protein / metabolism
Xenograft Model Antitumor Assays
beta Catenin / metabolism

Substances

ASCL2 protein, human
Antineoplastic Agents
Basic Helix-Loop-Helix Transcription Factors
CTNNB1 protein, human
Foxy-5 peptide
Intracellular Signaling Peptides and Proteins
Oligopeptides
WNT5A protein, human
Wnt-5a Protein
beta Catenin
Hydroxyprostaglandin Dehydrogenases
15-hydroxyprostaglandin dehydrogenase
Cyclooxygenase 2
PTGS2 protein, human
Aldehyde Dehydrogenase 1 Family
Aldehyde Dehydrogenase
ALDH1A1 protein, human
Retinal Dehydrogenase
DCLK1 protein, human
Doublecortin-Like Kinases
Protein Serine-Threonine Kinases
Dinoprostone