Cyclooxygenase inhibition in early onset of tumor growth and related angiogenesis evaluated in EP1 and EP3 knockout tumor-bearing mice

Abstract

It is well established that prostanoids are essential for local inflammation including cell proliferation and apoptosis. Accordingly, prostaglandin E2 (PGE(2)) is a critical factor in wound healing, tumor invasiveness and progression. Therefore, the aim of the present work was to evaluate effects by PGE(2) on tumor vascular density at early onset of tumor growth where hypoxia is limited. Wild-type mice (C57Bl, C3H/HeN) bearing either MCG-101 tumors or a malignant melanoma (K1735-M2) with either high or insignificant PGE(2) production and subsequently different in sensitivity to cyclooxygenase (COX) inhibition were used. Tumor angiogenesis was estimated by intravital microscopy and immune histochemical analysis in wild type and EP(1) or EP(3) subtype receptor knockout mice (C57Bl). Both MCG-101 and K1735-M2 tumor cells stimulated early outgrowth of tumor vessels in proportion to intrinsic growth rate of tumor cells. Indomethacin had no effects on tumor growth or tumor related vascular area in K1735-M2 bearing mice. By contrast, indomethacin decreased tumor cell proliferation and increased apoptosis in MCG-101 tumors with subsequent adaptation in tumor vascular density. Effects of indomethacin on early growth of MCG-101 tumors were not related to tumor content of bFGF protein, while our earlier studies on long-term tumor growth have shown decreased mRNA levels of bFGF during indomethacin treatment. Early onset of tumor growth was significantly promoted in EP(3)- but not in EP(1)-knockouts, although long-term tumor growth is attenuated in EP(1)-knockouts as reported elsewhere. Our results demonstrate that tumor production of PGE(2) promotes primarily net growth of tumor cells with subsequent adaptations in development of the tumor vasculature. Therefore, it is likely that angiogenesis is not a limiting step at the early onset of tumor growth.

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…In the azoxymethane colon cancer model, formation of aberrant crypt foci was reduced by approximately 40% in EP 1 (Ϫ/Ϫ) mice (Watanabe et al, 1999), and the number of tumors formed was essentially halved (Kawamori et al, 2005). In the methylcholanthrene-induced sarcoma model (MGC 101 mice), long-term growth was attenuated in EP 1 -deficient mice (Axelsson et al, 2005;Wang et al, 2005). The effects of cyclooxygenase inhibition on tumor progression were primarily on cell proliferation and apoptosis; angiogenesis was not an obvious primary determinant of onset and progression of tumor development (Axelsson et al, 2005).…”

“…In the methylcholanthrene-induced sarcoma model (MGC 101 mice), long-term growth was attenuated in EP 1 -deficient mice (Axelsson et al, 2005;Wang et al, 2005). The effects of cyclooxygenase inhibition on tumor progression were primarily on cell proliferation and apoptosis; angiogenesis was not an obvious primary determinant of onset and progression of tumor development (Axelsson et al, 2005).…”

Endothelin-1 and Endothelin-3 Promote Invasive Behavior via Hypoxia-Inducible Factor-1α in Human Melanoma Cells

“…The COX-1 and COX-2 enzymes are involved in tumor progression by inducing proliferation, survival, angiogenesis, invasion, and metastasis in several solid tumors (27)(28)(29)(30)(31)(32)(41)(42)(43)(44). To elucidate the regulatory mechanisms that underlie COX-1/COX-2 regulation, we identify COX enzymes as downstream signals of ETs/ET B R pathway, providing evidence that ET-1 and ET-3 induced COX-2 promoter activity and COX-1/COX-2 expression with resulting PGE 2 production.…”

“…Cyclooxygenase (COX)-2 is overexpressed in various types of cancers, including melanoma (27), and compelling evidence supports a role for COX-2 and COX-2-derived prostaglandin E 2 (PGE 2 ) in angiogenesis (28,29) and melanoma progression (30)(31)(32). However, the mechanisms that regulate transcriptional activation of COX-2, angiogenesis, and invasiveness in low-oxygen conditions have not been determined.…”

Prostaglandin E2-EP4 Receptor Promotes Endothelial Cell Migration via ERK Activation and Angiogenesis in Vivo

“…Similarly, EP3-null mice exhibit decreased tumor growth and tumor-associated angiogenesis compared with wild type mice following injection of sarcoma or lung carcinoma cells (10). In contrast, the EP1 receptor does not appear to play a role in tumor-associated angiogenesis (11) and, with the exception of one in vivo study (12), there is scant information on the direct role of EP4 receptor in angiogenesis and endothelial cell function.…”