Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin
Standard
Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin. / Meier, Claudia; Spitschak, Alf; Abshagen, Kerstin; Gupta, Shailendra; Mor, Joel M; Wolkenhauer, Olaf; Haier, Jörg; Vollmar, Brigitte; Alla, Vijay; Pützer, Brigitte M.
In: J PATHOL, Vol. 234, No. 3, 11.2014, p. 351-64.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin
AU - Meier, Claudia
AU - Spitschak, Alf
AU - Abshagen, Kerstin
AU - Gupta, Shailendra
AU - Mor, Joel M
AU - Wolkenhauer, Olaf
AU - Haier, Jörg
AU - Vollmar, Brigitte
AU - Alla, Vijay
AU - Pützer, Brigitte M
N1 - Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2014/11
Y1 - 2014/11
N2 - 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-β1-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.
AB - 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-β1-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.
KW - Animals
KW - Antigens, CD44
KW - Blotting, Western
KW - Cell Line, Tumor
KW - Chromatin Immunoprecipitation
KW - E2F1 Transcription Factor
KW - Enzyme-Linked Immunosorbent Assay
KW - Extracellular Matrix Proteins
KW - Fibronectins
KW - Fluorescent Antibody Technique
KW - Gene Expression Regulation, Neoplastic
KW - Heterografts
KW - Humans
KW - Immunoprecipitation
KW - Mice
KW - Neoplasm Invasiveness
KW - Neoplastic Cells, Circulating
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Transcription, Genetic
KW - Up-Regulation
U2 - 10.1002/path.4400
DO - 10.1002/path.4400
M3 - SCORING: Journal article
C2 - 25042645
VL - 234
SP - 351
EP - 364
JO - J PATHOL
JF - J PATHOL
SN - 0022-3417
IS - 3
ER -
