Autotaxin and Lysophosphatidic Acid Receptors as Novel Targets for the Radiosensitization of Tumor Vasculature in Non-Small Cell Lung Cancer
Amanda G. Linkous, Dennis E. Hallahan and Eugenia M. Yazlovitskaya
Pages 72-80 (9)
Despite advances in cancer treatment protocols, non-small cell lung cancer continues to be refractory to conventional
radiation therapy. This resistance to ionizing radiation is often determined by the response of the tumor vasculature.
Thus, a significant need exists for the development of novel and effective anti-angiogenic radiosensitizing agents.
The combined findings in this study identify autotaxin and lysophosphatidic acid as integral signaling components in irradiated
non-small cell lung cancer models. Our data show that co-cultures of vascular endothelial cells and lung cancer
cells produce lysophosphatidic acid (LPA) in response to ionizing radiation (3 Gy), which correlates with the level of
autotaxin secretion. Furthermore, conditioned medium from autotaxin-secreting lung tumor cells stimulates phosphorylation
of pro-survival kinases in irradiated vascular endothelium. Using an analog of lysophosphatidic acid, α-
bromomethylene phosphonate (BrP-LPA), we demonstrate that the chemical inhibition of autotaxin and LPA-specific receptors
results in reduced endothelial invasion and attenuated tumor cell migration. Together, these results suggest that
targeting autotaxin-mediated signaling pathways regulating tumor angiogenesis may improve the response of non-small
cell lung cancer to radiation therapy.
Autotaxin, invasion, lysophosphatidic acid, migration, non-small cell lung cancer, radiation, vascular endothelium
Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, C3210 Medical Center North 1161 21st Ave South, Nashville, TN 37232, USA.