CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation.
Colorectal cancer (CRC) is characterized by a distinct metastatic pattern resembling chemokine-induced leukocyte trafficking. This prompted us to investigate expression, signal transduction and specific functions of the chemokine receptor CXCR4 in CRC cells and metastases. Using RT-PCR analysis and Western blotting, we demonstrated CXCR4 and CXCL12 expression in CRC and CRC metastases. Cell differentiation increases CXCL12 mRNA levels. Moreover, CXCR4 and its ligand are inversely expressed in CRC cell lines with high CXCR4 and low or not detectable CXCL12 expression. CXCL12 activates ERK-1/2, SAPK/JNK kinases, Akt and matrix metalloproteinase-9. These CXCL12-induced signals mediate reorganization of the actin cytoskeleton resulting in increased cancer cell migration and invasion. Moreover, CXCL12 increases vascular endothelial growth factor (VEGF) expression and cell proliferation but has no effect on CRC apoptosis. Therefore, the CXCL12/CXCR4 system is an important mediator of invasion and metastasis of CXCR4 expressing CRC cells.
Brand
Stephan
S
Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany. stephan.brand@med.uni-muenchen.de
Dambacher
Julia
J
Beigel
Florian
F
Olszak
Torsten
T
Diebold
Joachim
J
Otte
Jan-Michel
JM
Göke
Burkhard
B
Eichhorst
Sören T
ST
D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D042442:Vascular Endothelial Growth Factors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9