title: Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis.
abstract: The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors.
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inada
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Department of Pharmacology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Morichika
authors.initials: M
authors.lastname: Takita
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Tominari
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Matsumoto
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Hirata
authors.affiliation: the Department of Pharmacology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maru
authors.affiliation: the Minase Research Institutes, Ono Pharmaceutical Co. Ltd, Osaka 618-8585, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: the Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: the Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, the Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba 260-8670, Japan, the Division of Innate Immune, Regulation, International Research, and Development, Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.affiliation: the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Department of Oncology, University of Cambridge, Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom, and.
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.affiliation: the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.affiliation: From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, miyaura@cc.tuat.ac.jp.
authors.forename: Chisato
authors.initials: C
authors.lastname: Miyaura
mesh_terms: D000818:Animals; D002455:Cell Division; D015232:Dinoprostone / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology*
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone
keywords: B16 melanoma; Bone resorption; EP4 receptor; angiogenesis; bone; host-cancer interaction; metastasis; prostaglandin; prostaglandin E; tumor microenvironment