COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer.
Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE2. Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors.
Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario, Canada N6A5C1.
A V
AV
Timoshenko
C
C
Chakraborty
G F
GF
Wagner
P K
PK
Lala
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D042583:Lymphangiogenesis / Q000502:physiology*; D008969:Molecular Sequence Data; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000378:metabolism / Q000502:physiology; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013329:Structure-Activity Relationship; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D033921:Vesicular Transport Proteins
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D016861:Cyclooxygenase Inhibitors; D006023:Glycoproteins; D007093:Imidazoles; C119248:LYVE1 protein, human; C545635:PTGER1 protein, human; C545650:PTGER4 protein, human; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; D051546:Cyclooxygenase 2; C093642:SB 203580; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline