COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems.
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.
Katoh
Hiroshi
H
Department of Pharmacology, Kitasato University, School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa, 228-8555, Japan.
Hosono
Kanako
K
Ito
Yoshiya
Y
Suzuki
Tatsunori
T
Ogawa
Yasufumi
Y
Kubo
Hidefumi
H
Kamata
Hiroki
H
Mishima
Toshiaki
T
Tamaki
Hideaki
H
Sakagami
Hiroyuki
H
Sugimoto
Yukihiko
Y
Narumiya
Shuh
S
Watanabe
Masahiko
M
Majima
Masataka
M
D000287:Administration, Topical; D000818:Animals; D057134:Antibodies, Neutralizing; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000008:administration & dosage / Q000494:pharmacology; D004338:Drug Combinations; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D057134:Antibodies, Neutralizing; D054377:Chemokine CXCL12; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C545648:Ptger3 protein, mouse; C545651:Ptger4 protein, mouse; D019718:Receptors, CXCR4; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C059485:matrigel; D003094:Collagen; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone