TY - JOUR
T1 - Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis
AU - Kubo, Hidefumi
AU - Hosono, Kanako
AU - Suzuki, Tatsunori
AU - Ogawa, Yasufumi
AU - Kato, Hiroshi
AU - Kamata, Hiroki
AU - Ito, Yoshiya
AU - Amano, Hideki
AU - Kato, Tetsuki
AU - Sakagami, Hiroyuki
AU - Hayashi, Izumi
AU - Sugimoto, Yukihiko
AU - Narumiya, Shuh
AU - Watanabe, Masahiko
AU - Majima, Masataka
N1 - Funding Information:
We thank Michiko Ogino, Kyoko Yoshikawa, and Osamu Katsumata for their technical assistance. We are also grateful to Dr. Patrick Hughes for linguistic assistance in the preparation of the manuscript. This study was supported by grants MEXT (2/390072, 20659037 and 20659093) and AKPS.
PY - 2010/2
Y1 - 2010/2
N2 - Prostaglandin E2 (PGE2) 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 PGE2 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.
AB - Prostaglandin E2 (PGE2) 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 PGE2 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.
KW - COX-2
KW - Cancer
KW - Eicosanoid
KW - VEGF-C
KW - VEGFR-3
UR - https://www.scopus.com/pages/publications/77349125367
U2 - 10.1016/j.biopha.2009.04.039
DO - 10.1016/j.biopha.2009.04.039
M3 - Article
C2 - 20034758
AN - SCOPUS:77349125367
SN - 0753-3322
VL - 64
SP - 101
EP - 106
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
IS - 2
ER -