Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis.
Prostaglandin E(2) (PGE(2)) and prostaglandin E (EP) receptor signaling pathways have been implicated in the promotion of tumor growth and angiogenesis. However, little is known about their roles in lymphangiogenesis during tumor development. The present study evaluates whether endogenous PGE(2) exhibits a critical role in tumor-associated lymphangiogenesis. Treatment of male C57BL/6 mice with a cyclooxygenase-2 inhibitor, celecoxib, for seven days resulted in a 52.4% reduction in tumor size induced by subcutaneous injection of murine Lewis lung cells. Celecoxib treatment down-regulated the expression of vascular endothelial growth factor receptor (VEGFR)-3 in stromal tissues by 73.9%, and attenuated expression of podoplanin, a marker for lymphatic endothelial cells. To examine the role of host PGE receptor signaling, we tested four kinds of EP receptor knockout mice. At Day 7 after tumor cell implantation, EP3 receptor knockout mice, but not EP receptor knockout mice lacking EP1, EP2, or EP4, exhibited a 53.3% reduction in tumor weight, which was associated with a 74.5% reduction in VEGFR-3 mRNA expression in tumor stromal tissues. At Day 14, VEGFR-3 expression in EP3-/- mice remained significantly lower than that of their wild-type (WT) counterparts. The expression of VEGF-C in the tumor stromal tissues in EP3-/- mice were also reduced by 22.1% (Day 7) and 44.1% (Day 14), respectively. In addition, the level of immunoreactive podoplanin in the tumor tissues from EP3-/- mice was less than that of WT. These results suggest that host EP3 receptor signaling regulates tumor-associated lymphangiogenesis by up-regulating expression of VEGF-C and its receptor, VEGFR-3, in tumor stromal tissues. Host EP3 blockade together with COX-2 inhibition may be a novel therapeutic strategy to suppress tumor-associated lymphangiogenesis.
Kubo
Hidefumi
H
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
Hosono
Kanako
K
Suzuki
Tatsunori
T
Ogawa
Yasufumi
Y
Kato
Hiroshi
H
Kamata
Hiroki
H
Ito
Yoshiya
Y
Amano
Hideki
H
Kato
Tetsuki
T
Sakagami
Hiroyuki
H
Hayashi
Izumi
I
Sugimoto
Yukihiko
Y
Narumiya
Shuh
S
Watanabe
Masahiko
M
Majima
Masataka
M
D000818:Animals; D000068579:Celecoxib; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D042583:Lymphangiogenesis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000098853:Podoplanin
D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D008562:Membrane Glycoproteins; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D040262:Receptors, Vascular Endothelial Growth Factor; D013449:Sulfonamides; C490441:Pdpn protein, mouse; D000098853:Podoplanin