論文 - 詳細
| RRC ID | 38186 |
|---|---|
| 著者 | Katoh H, Hosono K, Ito Y, Suzuki T, Ogawa Y, Kubo H, Kamata H, Mishima T, Tamaki H, Sakagami H, Sugimoto Y, Narumiya S, Watanabe M, Majima M. |
| タイトル | COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems. |
| ジャーナル | Am J Pathol |
| Abstract |
Bone marrow (BM)-derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)-2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3-/- mice and EP4-/- mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4+ fibroblasts, CXCL12+, and/or CXCR4+ stromal cells as well. Immunofluorescent analyses revealed that CXCL12+CXCR4+S100A4+ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE2-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins. |
| 巻・号 | 176(3) |
| ページ | 1469-83 |
| 公開日 | 2010-3-1 |
| DOI | 10.2353/ajpath.2010.090607 |
| PII | S0002-9440(10)60458-0 |
| PMID | 20110411 |
| PMC | PMC2832166 |
| MeSH | Administration, Topical Animals Antibodies, Neutralizing Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism Bone Marrow Cells / pathology Cell Movement / drug effects Chemokine CXCL12 / metabolism* Collagen / metabolism Cyclooxygenase 2 / metabolism* Dinoprostone / administration & dosage Dinoprostone / pharmacology Drug Combinations Fibroblasts / drug effects Fibroblasts / metabolism Fibroblasts / pathology Granulation Tissue / drug effects Granulation Tissue / pathology Laminin / metabolism Male Mice Mice, Inbred C57BL Neoplasm Transplantation Neoplasms / blood supply* Neoplasms / enzymology Neoplasms / pathology Neovascularization, Pathologic / enzymology* Neovascularization, Pathologic / pathology Proteoglycans / metabolism Receptors, CXCR4 / metabolism* Receptors, Prostaglandin E / agonists Receptors, Prostaglandin E / metabolism* Receptors, Prostaglandin E, EP3 Subtype Receptors, Prostaglandin E, EP4 Subtype Signal Transduction / drug effects Stromal Cells / drug effects Stromal Cells / enzymology Stromal Cells / pathology |
| IF | 3.491 |
| 引用数 | 68 |
| WOS 分野 | PATHOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | |