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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin
Journal of Pathology, Volume 234, No. 3, Year 2014
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Description
Dissemination of cancer cells from primary to distant sites is a complex process; little is known about the genesis of metastatic changes during disease development. Here we show that the metastatic potential of E2F1-dependent circulating tumour cells (CTCs) relies on a novel function of the hyaluronan-mediated motility receptor RHAMM. E2F1 directly up-regulates RHAMM, which in turn acts as a co-activator of E2F1 to stimulate expression of the extracellular matrix protein fibronectin. Enhanced fibronectin secretion links E2F1/RHAMM transcriptional activity to integrin-1-FAK signalling associated with cytoskeletal remodelling and enhanced tumour cell motility. RHAMM depletion abolishes fibronectin expression and cell transmigration across the endothelial layer in E2F1-activated cells. In a xenograft model, knock-down of E2F1 or RHAMM in metastatic cells protects the liver parenchyma of mice against extravasation of CTCs, whereas the number of transmigrated cells increases in response to E2F1 induction. Expression data from clinical tissue samples reveals high E2F1 and RHAMM levels that closely correlate with malignant progression. These findings suggest a requirement for RHAMM in late-stage metastasis by a mechanism involving cooperative stimulation of fibronectin, with a resultant tumourigenic microenvironment important for enhanced extravasation and distant organ colonization. Therefore, stimulation of the E2F1-RHAMM axis in aggressive cancer cells is of high clinical significance. Targeting RHAMM may represent a promising approach to avoid E2F1-mediated metastatic dissemination. © 2014 Pathological.
Authors & Co-Authors
Spitschak, Alf
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Gupta, Shailendra Kumar
Germany, Rostock
Universität Rostock
Wolkenhauer, Olaf
Germany, Rostock
Universität Rostock
Haier, J.
Germany, Munster
Universitätsklinikum Münster
Vollmar, Brigitte
Unknown Affiliation
Pützer, Brigitte M.
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Statistics
Citations: 37
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1002/path.4400
ISSN:
00223417
Research Areas
Cancer