title: Platelet-activating factor and metastasis: calcium-independent phospholipase A2β deficiency protects against breast cancer metastasis to the lung.
abstract: We determined the contribution of calcium-independent phospholipase A(2)β (iPLA(2)β) to lung metastasis development following breast cancer injection into wild-type (WT) and iPLA(2)β-knockout (iPLA(2)β-KO) mice. WT and iPLA(2)β-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)β-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)β-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-α (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-α (60.5 ± 4.3, P < 0.01). These responses were blocked by pretreatment with the iPLA(2)β-selective inhibitor (S)-bromoenol lactone and absent in lung endothelial cells from iPLA(2)β-KO mice. These data indicate that endothelial cell iPLA(2)β is responsible for PAF production and adherence of E0771 cells and may play a role in cancer cell migration to distal locations.
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, Missouri 63104, USA. mchowaj@slu.edu
authors.forename: Jane
authors.initials: J
authors.lastname: McHowat
authors.forename: Gail
authors.initials: G
authors.lastname: Gullickson
authors.forename: Richard G
authors.initials: RG
authors.lastname: Hoover
authors.forename: Janhavi
authors.initials: J
authors.lastname: Sharma
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Jacki
authors.initials: J
authors.lastname: Kornbluth
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D054513:Group IV Phospholipases A2 / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008168:Lung / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000503:physiopathology* / Q000517:prevention & control; D009368:Neoplasm Transplantation; D010972:Platelet Activating Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D054513:Group IV Phospholipases A2