Platelet-activating factor and metastasis: calcium-independent phospholipase A2β deficiency protects against breast cancer metastasis to the lung

McHowat J, Gullickson G, Hoover RG, Sharma J, Turk J, Kornbluth J. Platelet-activating factor and metastasis: calcium-independent phospholipase A(2)beta deficiency protects against breast cancer metastasis to the lung. Am J Physiol Cell Physiol 300: C825-C832, 2011. First published January 12, 2011; doi:10.1152/ajpcell.00502.2010.-We determined the contribution of calcium-independent phospholipase A(2)beta (iPLA(2)beta) to lung metastasis development following breast cancer injection into wild-type (WT) and iPLA(2)beta-knockout (iPLA(2)beta-KO) mice. WT and iPLA(2)beta-KO mice were injected in the mammary pad with 200,000 E0771 breast cancer cells. There was no difference in primary tumor size between WT and iPLA(2)beta-KO mice at 27 days postinjection. However, we observed an 11-fold greater number of breast cancer cells in the lungs of WT mice compared with iPLA(2)beta-KO animals (P < 0.05). Isolated WT lung endothelial cells demonstrated a significant increase in platelet-activating factor (PAF) production when stimulated with thrombin [1 IU/ml, 10 min, 4,330 +/- 555 vs. 15,227 +/- 1,043 disintegrations per minute (dpm), P < 0.01] or TNF-alpha (10 ng/ml, 2 h, 16,532 +/- 538 dpm, P < 0.01). Adherence of E0771 cells to WT endothelial cells was increased by thrombin (4.8 +/- 0.3% vs. 70.9 +/- 6.3, P < 0.01) or TNF-alpha (60.5 +/- 4.3, P < 0.01). These responses were blocked by pretreatment with the iPLA(2)beta-selective inhibitor (S)-bromoenol lactone and absent in lung endothelial cells from iPLA(2)beta-KO mice. These data indicate that endothelial cell iPLA(2)beta is responsible for PAF production and adherence of E0771 cells and may play a role in cancer cell migration to distal locations.