Lysophosphatidic acid receptor expression in chronic lymphocytic leukemia leads to cell survival mediated though vascular endothelial growth factor expression

Abstract

Lysophosphatidic acid (LPA) protects chronic lymphocytic leukemia (CLL) cells from apoptosis. Vascular endothelial growth factor (VEGF) also protects CLL cells against apoptosis. The mechanism for LPA protection against apoptosis in CLL cells is unknown. Herein, we show CLL cells express LPA receptors LPA_1–5 but in normal B cells, LPA₁ was rarely expressed and LPA_3, LPA_4, and LPA₆ were undetectable whereas the other LPA receptors were expressed. LPA plasma levels are similar in patients with CLL compared to healthy controls. In contrast, plasma levels of VEGF are elevated in patients with CLL compared to healthy controls and LPA treatment induced VEGF secretion in CLL cells. CLL cells also express VEGF receptors and LPA protection against Flu induced apoptosis is blocked by inhibition of VEGF receptor activation. These results indicate that LPA protects CLL cells from apoptosis through higher expression of LPA receptors and autocrine production of VEGF.

Keywords:

• LPA
• VEGF
• apoptosis
• and chronic lymphocytic leukemia (CLL)

Acknowledgements

The authors would like to thank Dr. Frank Fang for the kind gift of reagents. This work was supported by funds from the Leukemia and Lymphoma Society. S.B.G. holds a Manitoba Research Chair and A.K. holds a fellowship from the Manitoba Health Research Council. Primary CLL sample was provided by the Manitoba CLL Tissue Bank. This research was also financially supported by the CancerCare Manitoba Translational Research Program and CancerCare Manitoba Foundation.