| 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
|
| リソース情報 |
| ヒト・動物細胞 |
|
