CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins.
The mechanisms leading to prostate cancer metastasis are not understood completely. Although there is evidence that the CXC chemokine receptor (CXCR) 4 and its ligand CXCL12 may regulate tumor dissemination, their role in prostate cancer is controversial. We examined CXCR4 expression and functionality, and explored CXCL12-triggered adhesion of prostate tumor cells to human endothelium or to extracellular matrix proteins laminin, collagen, and fibronectin. Although little CXCR4 was expressed on LNCaP and DU-145 prostate tumor cells, CXCR4 was still active, enabling the cells to migrate toward a CXCL12 gradient. CXCL12 induced elevated adhesion to the endothelial cell monolayer and to immobilized fibronectin, laminin, and collagen. Anti-CXCR4 antibodies or CXCR4 knock out significantly impaired CXCL12-triggered tumor cell binding. The effects observed did not depend on CXCR4 surface expression level. Rather, CXCR4-mediated adhesion was established by alpha5 and beta3 integrin subunits and took place in the presence of reduced p38 and p38 phosphorylation. These data show that chemoattractive mechanisms are involved in adhesion processes of prostate cancer cells, and that binding of CXCL12 to its receptor leads to enhanced expression of alpha5 and beta3 integrins. The findings provide a link between chemokine receptor expression and integrin-triggered tumor dissemination.
Engl
Tobias
T
Zentrum der Chirurgie, Klinik für Urologie und Kinderurologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Relja
Borna
B
Marian
Dana
D
Blumenberg
Christa
C
Müller
Iris
I
Beecken
Wolf-Dietrich
WD
Jones
Jon
J
Ringel
Eva M
EM
Bereiter-Hahn
Jürgen
J
Jonas
Dietger
D
Blaheta
Roman A
RA
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis*; D039661:Integrin beta3 / Q000096:biosynthesis*; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039482:Integrin alpha5; D039661:Integrin beta3; D019718:Receptors, CXCR4; D048051:p38 Mitogen-Activated Protein Kinases