RRC ID 38186
Author 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.
Title COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems.
Journal 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.
Volume 176(3)
Pages 1469-83
Published 2010-3
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 4.069
Times Cited 51
Human and Animal Cells