CLL, but not normal, B cells are dependent on autocrine VEGF and alpha4beta1 integrin for chemokine-induced motility on and through endothelium.
Vascular endothelial cell growth factor (VEGF) is a multifunctional cytokine involved in tumor formation. In chronic lymphocytic leukemia (CLL), it is known that the malignant cells secrete VEGF and possess VEGF receptors. This suggests that an autocrine loop might be important in the pathogenesis of CLL. Here we show that, in patients with lymphadenopathy, autocrine VEGF and alpha(4)beta(1) integrin are involved in the chemokine-dependent motility of CLL cells on and through endothelium-processes important for the invasion of lymphoreticular tissues, a major determinant of disease outcome. In contrast, normal lymphocytes were not dependent on autocrine VEGF or alpha(4)beta(1) for either type of cell movement. Moreover, in contrast to normal B lymphocytes, CLL cells failed to cluster and activate alpha(L)beta(2) in response to chemokines, unless VEGF receptor(s) and alpha(4)beta(1) were also engaged by their respective ligands. This is the first demonstration that autocrine VEGF is involved in CLL-cell motility, and that the alpha(L)beta(2) on the malignant cells is functionally altered compared with that of normal B cells in not undergoing activation in response to chemokine alone. Given the importance of cell motility for tissue invasion, the present results provide a rationale for a trial of VEGF and alpha(4) blockade in patients with CLL who have tissue disease.
Till
Kathleen J
KJ
Department of Haematology, University of Liverpool, United Kingdom. k.j.till@liv.ac.uk
Spiller
David G
DG
Harris
Robert J
RJ
Chen
Haijuan
H
Zuzel
Mirko
M
Cawley
John C
JC
D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009361:Neoplasm Invasiveness; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D003432:Cross-Linking Reagents; D039041:Integrin alpha4beta1; D016023:Integrins; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A