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.