title: Prostanoid induces premetastatic niche in regional lymph nodes.
abstract: The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2-derived prostaglandin E2 (PGE2) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell-derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE2 receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. Compared with WT CD11c+ DCs, injection of EP3-deficient CD11c+ DCs dramatically reduced accumulation of SDF-1+CD11c+ DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, which may influence the fate of metastasized tumor cells, was also COX-2/EP3-dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1 and suggest that inhibition of this signaling axis may be an effective strategy to suppress premetastatic niche formation and LNM.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ogawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Matsui
authors.forename: Kanako
authors.initials: K
authors.lastname: Hosono
authors.forename: Hidero
authors.initials: H
authors.lastname: Kitasato
authors.forename: Akira
authors.initials: A
authors.lastname: Iyoda
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwabuchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Satoh
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D015232:Dinoprostone / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D055786:Gene Knockout Techniques; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D052246:Cyclooxygenase 2 Inhibitors; C545648:Ptger3 protein, mouse; D011720:Pyrazoles; D019718:Receptors, CXCR4; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone