Prostanoid receptor signaling relevant to tumor growth and angiogenesis

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Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit the cyclooxygenases (COXs) and suppress prostaglandin (PG) synthesis have been used widely as anti-inflammatory, antipyretic and analgesic agents. Recent epidemiological studies have established that the long-term intake of NSAIDs reduces the risk of colorectal cancer. Despite the efficacy of NSAIDs as anticancer agents, the precise mechanism(s) of their protective effect remain(s) unknown. A wide range of mechanisms have been proposed to account for the antitumor actions of NSAIDs, some of which are unrelated to the inhibition of COX activity and subsequent PG formation. However, recent results from knockout mice indicate that prostanoid receptor signaling enhances tumor-associated angiogenesis and tumor growth. Here, we discuss the significance of PGE2 signaling via prostanoid receptors, such as EP3 receptors, on the host stroma but not on tumor cells themselves. Agents that block these receptor signaling events are promising novel therapeutic tools for malignant tumors.

Section snippets

Angiogenesis as a target of NSAIDs

Angiogenesis is an important factor in tumor development and tumor-associated angiogenesis is mediated by the migration and proliferation of host endothelial cells. Substantial increases in tumor mass must be preceded by an increase in blood supply to provide the nutrients and oxygen required for tumor growth and it has been suggested that the mechanisms that promote angiogenesis are activated in the early stages of tumor development [20]. Although the significance of COX-2 as a target for

The prostanoid receptor subtype responsible for angiogenesis in vivo

PGs exert their biological actions by binding to specific receptors that contain seven transmembrane domains. Eight different prostanoid receptors have been defined pharmacologically and cloned, including the DP receptor (PGD receptor), four subtypes of the EP (PGE) receptor (EP1, EP2, EP3 and EP4 receptors), the FP receptor (PGF receptor), the IP receptor (PGI receptor) and the TP receptor (TX receptor) [13]. Genes for each of these receptors have been disrupted and corresponding knockout mice

Prostanoid receptor antagonism as a promising preventive approach for cancer and the control of inflammatory responses in the tumor microenvironment

As discussed previously, highly selective EP3- and EP2 receptor antagonists exhibit beneficial effects on stromal cells and might be a good choice as novel therapeutic tools against cancer. Administration of an EP3 receptor antagonist to wild-type mice that bear tumors significantly suppresses tumor-associated angiogenesis and tumor growth [19]. By contrast, this was not observed following administration of antagonists selective for EP1 and EP4 receptors 16, 43. Furthermore, the preventive

Acknowledgements

This work was supported by grants from an Integrative Research Program of the Graduate School of Medical Sciences, Kitasato University and a Parents' Association Grant of Kitasato University, School of Medicine, and also by research grants (#15390084), ‘High-tech Research Center’ grant, and a grant from the 21st Century COE Program, from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

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