CLL Cells use VEGF to Move through Endothelium Layer in Blood Vessels

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Blood First Edition Paper, prepublished online February 24, 2005

Submitted October 21, 2004

Accepted February 18, 2005

CLL, but not normal, B cells are dependent on autocrine VEGF and 41

integrin for chemokine-induced motility on and through endothelium

Kathleen J Till, G Spiller, J , Haijuan Chen,

Mirko Zuzel, and C Cawley

Department of Haematology, University of Liverpool, Liverpool, United

Kingdom

Center for Cell Imaging, University of Liverpool, Liverpool, United

Kingdom

Vascular endothelial cell growth factor (VEGF) is a multifunctional

cytokine involved in tumour formation. In chronic lymphocytic

leukaemia (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 41-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 41 for either type of cell movement. Moreover, in contrast to

normal B lymphocytes, CLL cells failed to cluster and activate L2 in

response to chemokines, unless VEGF receptor(s) and 41 were also

engaged by their respective ligands.

This is the first demonstration that autocrine VEGF is involved in

CLL-cell motility, and that the L2 on the malignant cells is

functionally altered as 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 trail of VEGF and 4

blockade in CLL patients with tissue disease.

*the layer of cells lining blood vessels.

**lymph nodes, spleen, thymus and mucosa- association lymphoid tissue

(MALT)