CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells.
Authors
Southgate, Thomas DMcGinn, Owen J
Castro, Fernanda V
Rutkowski, Andrzej J
Al-Muftah, Mariam
Marinov, Georgi
Smethurst, Graeme J
Shaw, David M
Ward, Christopher M
Miller, Crispin J
Stern, Peter L
Affiliation
Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.Issue Date
2010
Metadata
Show full item recordAbstract
5T4 oncofetal molecules are highly expressed during development and upregulated in cancer while showing only low levels in some adult tissues. Upregulation of 5T4 expression is a marker of loss of pluripotency in the early differentiation of embryonic stem (ES) cells and forms an integrated component of an epithelial-mesenchymal transition, a process important during embryonic development and metastatic spread of epithelial tumors. Investigation of the transcriptional changes in early ES differentiation showed upregulation of CXCL12 and down-regulation of a cell surface protease, CD26, which cleaves this chemokine. CXCL12 binds to the widely expressed CXCR4 and regulates key aspects of development, stem cell motility and tumour metastasis to tissues with high levels of CXCL12. We show that the 5T4 glycoprotein is required for optimal functional cell surface expression of the chemokine receptor CXCR4 and CXCL12 mediated chemotaxis in differentiating murine embryonic stem cells and embryo fibroblasts (MEF). Cell surface expression of 5T4 and CXCR4 molecules is co-localized in differentiating ES cells and MEF. By contrast, differentiating ES and MEF derived from 5T4 knockout (KO) mice show only intracellular CXCR4 expression but infection with adenovirus encoding mouse 5T4 restores CXCL12 chemotaxis and surface co-localization with 5T4 molecules. A series of chimeric constructs with interchanged domains of 5T4 and the glycoprotein CD44 were used to map the 5T4 sequences relevant for CXCR4 membrane expression and function in 5T4KO MEF. These data identified the 5T4 transmembrane domain as sufficient and necessary to enable CXCR4 cell surface expression and chemotaxis. Furthermore, some monoclonal antibodies against m5T4 can inhibit CXCL12 chemotaxis of differentiating ES cells and MEF which is not mediated by simple antigenic modulation. Collectively, these data support a molecular interaction of 5T4 and CXCR4 occurring at the cell surface which directly facilitates the biological response to CXCL12. The regulation of CXCR4 surface expression by 5T4 molecules is a novel means to control responses to the chemokine CXCL12 for example during embryogenesis but can also be selected to advantage the spread of a 5T4 positive tumor from its primary site.Citation
CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells. 2010, 5 (4):e9982 PLoS OneJournal
PloS OneDOI
10.1371/journal.pone.0009982PubMed ID
20376365Type
ArticleLanguage
enISSN
1932-6203ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0009982
Scopus Count
Collections
Related articles
- CXCL12 receptor preference, signal transduction, biological response and the expression of 5T4 oncofoetal glycoprotein.
- Authors: McGinn OJ, Marinov G, Sawan S, Stern PL
- Issue date: 2012 Nov 15
- E-cadherin inhibits cell surface localization of the pro-migratory 5T4 oncofetal antigen in mouse embryonic stem cells.
- Authors: Spencer HL, Eastham AM, Merry CL, Southgate TD, Perez-Campo F, Soncin F, Ritson S, Kemler R, Stern PL, Ward CM
- Issue date: 2007 Aug
- The 5T4 oncofetal glycoprotein does not act as a general organizer of the CXCL12 system in cancer cells.
- Authors: Puchert M, Koch C, Engele J
- Issue date: 2018 Mar 15
- Understanding and exploiting 5T4 oncofoetal glycoprotein expression.
- Authors: Stern PL, Brazzatti J, Sawan S, McGinn OJ
- Issue date: 2014 Dec
- Epithelial-mesenchymal transition events during human embryonic stem cell differentiation.
- Authors: Eastham AM, Spencer H, Soncin F, Ritson S, Merry CL, Stern PL, Ward CM
- Issue date: 2007 Dec 1