| RRC ID |
45321
|
| 著者 |
Ogawa F, Amano H, Eshima K, Ito Y, Matsui Y, Hosono K, Kitasato H, Iyoda A, Iwabuchi K, Kumagai Y, Satoh Y, Narumiya S, Majima M.
|
| タイトル |
Prostanoid induces premetastatic niche in regional lymph nodes.
|
| ジャーナル |
J Clin Invest
|
| 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.
|
| 巻・号 |
124(11)
|
| ページ |
4882-94
|
| 公開日 |
2014-11-1
|
| DOI |
10.1172/JCI73530
|
| PII |
73530
|
| PMID |
25271626
|
| PMC |
PMC4347225
|
| MeSH |
Animals
Antineoplastic Agents / pharmacology
Carcinoma, Lewis Lung / immunology
Carcinoma, Lewis Lung / metabolism
Carcinoma, Lewis Lung / secondary*
Celecoxib
Cell Line, Tumor
Chemokine CXCL12 / metabolism
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / pharmacology
Dendritic Cells / immunology
Dinoprostone / physiology*
Drug Screening Assays, Antitumor
Gene Knockout Techniques
Lung Neoplasms / immunology
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Lymph Nodes / immunology
Lymph Nodes / pathology*
Lymphangiogenesis
Lymphatic Metastasis
Male
Mice, Knockout
Neoplasm Transplantation
Pyrazoles / pharmacology
Receptors, CXCR4 / metabolism
Receptors, Prostaglandin E, EP3 Subtype / genetics
Receptors, Prostaglandin E, EP3 Subtype / metabolism
Signal Transduction
Sulfonamides / pharmacology
T-Lymphocytes, Regulatory / immunology
|
| IF |
11.864
|
| 引用数 |
37
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
|
| リソース情報 |
| ヒト・動物細胞 |
LLC(RCB0558) |
