Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity

Abstract

The involvement of inflammation in cancer progression has been the subject of research for many years. Inflammatory milieu and immune response are associated with cancer progression and recurrence. In different types of tumors, growth and metastatic phenotype characterized by the epithelial mesenchymal transition (EMT) process, stemness, and angiogenesis, are increasingly associated with intrinsic or extrinsic inflammation. Among the inflammatory mediators, prostaglandin E2 (PGE2) supports epithelial tumor aggressiveness by several mechanisms, including growth promotion, escape from apoptosis, transactivation of tyrosine kinase growth factor receptors, and induction of angiogenesis. Moreover, PGE2 is an important player in the tumor microenvironment, where it suppresses antitumor immunity and regulates tumor immune evasion, leading to increased tumoral progression. In this review, we describe the current knowledge on the pro-tumoral activity of PGE2 focusing on its role in cancer progression and in the regulation of the tumor microenvironment.

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

“…PGE2 is secreted by both cancer cells and immune cells present in the TME, where it promotes the differentiation of MDSCs, from bone marrow progenitors, and DCs and their recruitment and activation, the M2 polarization of macrophages and their expression of programmed death ligand (PD-L)1. In addition, it suppresses NK anti-metastatic activity by reducing the expression of their activating receptors, stimulates the induction of Th2 cells and Tregs while inhibiting Th1 polarization, overall inducing immunosuppression (115). Besides chemokines, cytokines, and eicosanoids, an immunosuppressive role is also played by metabolites produced by cancer cells, such as adenosine.…”

“…Notably, chemokines such as CCL2, CCL5, CCL17, CCL18, CCL20 and CCL22, cytokines such as hepatocyte growth factor (HGF), PDGF-B, VEGF, IL-4, IL-10, prostaglandin (PG) and TGF-β and enzymes, such as Cathepsin K, cyclooxygenase-2 (COX-2), ARG1 and MMPs secreted by TAMs can directly inhibit both CD8 + and CD4 + T cell effector function as well as recruit Tregs into the tumor lesion ( 114 ). In particular, PGE2, the major product of COX-2, plays a pivotal role in BC progression, though the binding to seven transmembrane G-protein-coupled receptors expressed on several immune cell subsets ( 115 ). Inhibition of its production by unselective COX inhibitors such as aspirin or other non-steroidal anti-inflammatory drugs has been associated with a reduced risk of developing BC ( 116 ), which constitutively expresses high amounts of COX-2 ( 117 ).…”

Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

“…Their mechanisms in anticancer activities are not fully understood, but both COX-dependent and -independent pathways play a role. COX2-derived prostaglandin E2 (PGE2) can bind to its receptors on cancer cells and promote tumor cell proliferation, migration, angiogenesis, and chemoresistance [ 197 , 198 ]. Although the anticancer effects of many NSAIDs are attributable to inhibition of the COX2/PGE2 axis, additional mechanisms of action of NSAIDs have been characterized.…”

“…Published studies indicate that the antineoplastic activities of NSAIDs can also provoke antitumor immune responses. Inhibition of PGE2, a potent immunosuppressive factor enriched in the TME, leads to improved antitumor immunity [ 198 , 218 ]. Inhibition of phosphodiesterase 5 (PDE5) activity can abrogate MDSC-mediated immune suppression [ 219 , 220 ].…”

Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer

“…reported that Prostaglandin E2 can suppress IRF4 expression in T cells ( 40 ). Meanwhile, Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells ( 41 ). These studies suggest a possibility that a high level of prostaglandin E2 in the tumor microenvironment induces MDSCs development by suppressing IRF4 expression.…”