Prostacyclin Released by Cancer-Associated Fibroblasts Promotes Immunosuppressive and Pro-Metastatic Macrophage Polarization in the Ovarian Cancer Microenvironment

Abstract

Metastasis of high-grade ovarian carcinoma (HGSC) is orchestrated by soluble mediators of the tumor microenvironment. Here, we have used transcriptomic profiling to identify lipid-mediated signaling pathways encompassing 41 ligand-synthesizing enzymes and 23 cognate receptors in tumor, immune and stroma cells from HGSC metastases and ascites. Due to its strong association with a poor clinical outcome, prostacyclin (PGI2) synthase (PTGIS) is of particular interest in this signaling network. PTGIS is highly expressed by cancer-associated fibroblasts (CAF), concomitant with elevated PGI2 synthesis, whereas tumor-associated macrophages (TAM) exhibit the highest expression of its surface receptor (PTGIR). PTGIR activation by PGI2 agonists triggered cAMP accumulation and induced a mixed-polarization macrophage phenotype with altered inflammatory gene expression, including CXCL10 and IL12A repression, as well as reduced phagocytic capability. Co-culture experiments provided further evidence for the interaction of CAF with macrophages via PGI2, as the effect of PGI2 agonists on phagocytosis was mitigated by cyclooxygenase inhibitors. Furthermore, conditioned medium from PGI2-agonist-treated TAM promoted tumor adhesion to mesothelial cells and migration in a PTGIR-dependent manner, and PTGIR activation induced the expression of metastasis-associated and pro-angiogenic genes. Taken together, our study identifies a PGI2/PTGIR-driven crosstalk between CAF, TAM and tumor cells, promoting immune suppression and a pro-metastatic environment.

Identification of novel membrane markers in circulating tumor cells of mesenchymal state in breast cancer

“…Another study showed that F11R is participated in various biological processes, including paracellular permeability, tight junction formation and maintenance, leukocyte trans -endothelial migration, epithelial-to-mesenchymal transition, angiogenesis, reovirus binding, and platelet activation [ 21 ]. Similarly, PTGIR activation was shown to be associated with inducing the expression of metastasis-related or pro-angiogenic genes [ 22 ].…”

Identification of common factors among Fibrosarcoma, Rhabdomyosarcoma, and Osteosarcoma by network analysis

“…PTGIR has been found to be misregulated in several types of cancers, such as colorectal, ovarian, and melanoma. Studies have shown that the misregulation of PTGIR promotes tumor growth and metastasis (40,41). One gene, called LYVE1 (Lymphatic vessel endothelial hyaluronan receptor 1), encodes a receptor primarily expressed in lymphatic vessels and plays a role in lymphangiogenesis (42).…”

Arachidonic acid metabolism in health and disease

“…In addition to the direct effects of AA, its metabolites are also involved in the immunosuppressive effects of the tumor microenvironment 266 . PGI‐2 released by tumor‐associated fibroblasts was found to promote immunosuppression and metastatic macrophage polarization in the ovarian cancer microenvironment 267 . AA contributes to an unfavorable clinical outcome of OC by impacting the phenotype of tumor‐associated macrophages via the ASK1–p38δ/α (MAPK13/14) regulatory axis 268 .…”