Abstract
Signals mediated by CXCL12 (SDF1) and its receptor CXCR4 are centrally involved in cancer progression, both directly by activating cancer cells and indirectly by inducing angiogenesis plus recruiting T regulatory and plasmacytoid dendritic immune cells. Here, we show that in ascites isolated from ovarian cancer patients, both CXCL12 and CXCR4 are controlled by the tumor-associated inflammatory mediator prostaglandin E(2) (PGE(2)), which attracts myeloid-derived suppressor cells (MDSC) into the ascites microenvironment. In this setting, PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. Inhibition of COX2 or the PGE(2) receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. Similarly, COX2 inhibition also blocked CXCL12 production in the ovarian cancer environment and its ability to attract MDSCs. Together, our findings elucidate a central role for PGE(2) in MDSC accumulation triggered by the CXCL12-CXCR4 pathway, providing a powerful rationale to target PGE(2) signaling in ovarian cancer therapy.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Biphenyl Compounds / pharmacology
-
CD11b Antigen / genetics
-
CD11b Antigen / metabolism
-
Celecoxib
-
Cell Movement
-
Cells, Cultured
-
Chemokine CXCL12 / genetics
-
Chemokine CXCL12 / metabolism*
-
Cyclooxygenase 2 / genetics
-
Cyclooxygenase 2 / metabolism
-
Cyclooxygenase 2 Inhibitors / pharmacology
-
Dinoprostone / metabolism*
-
Female
-
Flow Cytometry
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Monocytes / drug effects
-
Monocytes / metabolism
-
Monocytes / pathology
-
Myeloid Cells / drug effects
-
Myeloid Cells / metabolism*
-
Myeloid Cells / pathology
-
Ovarian Neoplasms / genetics
-
Ovarian Neoplasms / metabolism*
-
Ovarian Neoplasms / pathology
-
Prostaglandin Antagonists / pharmacology
-
Pyrazoles / pharmacology
-
Receptors, CXCR4 / genetics
-
Receptors, CXCR4 / metabolism*
-
Receptors, Prostaglandin E, EP2 Subtype / antagonists & inhibitors
-
Receptors, Prostaglandin E, EP2 Subtype / metabolism
-
Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors
-
Sulfonamides / pharmacology
-
Tumor Cells, Cultured
-
Tumor Microenvironment / drug effects
-
Xanthones / pharmacology
Substances
-
Biphenyl Compounds
-
CD11b Antigen
-
CXCR4 protein, human
-
Chemokine CXCL12
-
Cyclooxygenase 2 Inhibitors
-
ITGAM protein, human
-
PTGER2 protein, human
-
Prostaglandin Antagonists
-
Pyrazoles
-
Receptors, CXCR4
-
Receptors, Prostaglandin E, EP2 Subtype
-
Receptors, Prostaglandin E, EP4 Subtype
-
Sulfonamides
-
Xanthones
-
6-isopropoxy-9-oxoxanthene-2-carboxylic acid
-
AH 23848
-
Cyclooxygenase 2
-
PTGS2 protein, human
-
Celecoxib
-
Dinoprostone