ReviewCOX-2 and PGE2-dependent immunomodulation in breast cancer
Highlights
► In this review, we discuss PGE2 immunomodulation of the tumor microenvironment. ► We particularly emphasize macrophage, MDSC, and Treg-based immunosuppression. ► Understanding PGE2-derived immunosuppression may lead to targeted cancer therapies.
Introduction
Cyclooxygenase (COX) is the enzyme responsible for the conversion of arachidonic acid into the various prostanoids, a family of lipid mediators that have widespread and diverse biological function [1]. COX exists in two main isoforms, COX-1, which is predominantly constitutive and responsible for generation of prostanoids for “housekeeping functions”, and COX-2, the inducible isoform, which contributes prostanoids involved in a variety of growth and inflammatory events [1], [2]. Synthesis of eicosanoids begins after the release of arachidonic acid (AA) from membrane phospholipids through the action of cytosolic phospholipase A2. COX-1/COX-2, also known as prostaglandin G/H synthase 1/2, converts AA into prostaglandin (PG) G2 and then reduces PGG2 to PGH2. PGH2 can be metabolized by the various PG synthases into PGD2, PGE2, PGF2α, PGI2, and thromboxane (TX) A2, which then act via distinct downstream G protein-coupled receptors.
A large body of work describing a link between inflammation and cancer [3] has generated intense interest in targeting COX enzymes, COX-2 in particular, for cancer therapy or chemoprevention. COX-2 is upregulated in 40% of breast cancers, with up to 84% increases in some studies [4]. Clinical studies have noted a reduced risk for breast, lung, prostate, and colon cancers after treatment with non-steroidal anti-inflammatory drugs (NSAIDs), which non-selectively inhibit COX-1 and COX-2, or with selective inhibition of COX-2 [5]. The beneficial effects of aspirin are less clear in part because many studies do not distinguish between consumption of low dose aspirin, whose effect is limited to inhibition of platelet COX-1 function, and higher doses that inhibit systemic function of both isozymes. In the Women's Health Initiative observational study, chronic regular use of NSAIDs was associated with reduced risk of breast cancer but subgroup analysis revealed no effect of low dose aspirin (<100 mg) [6]. Similarly, the Women's Health Study, a long term randomized trial, showed no effect of low dose aspirin every other day on breast cancer incidence [7]. Reduced risk of breast cancer death and distant recurrence, but not incidence of primary disease, was associated with regular aspirin use in the prospective observational Nurses’ Health Study but dose was not reported [8]. In contrast, in another recent study, lifetime aspirin use was associated with a 32% decreased risk of breast cancer, though, again, no information on dosage was collected [9]. Analysis of eight aspirin trials revealed reduced cancer death that was independent of dose across several common cancers although scant information was available in breast cancer [10].
Certain COX-2-derived products, particularly PGE2, are known to act via classical cancer signaling pathways in primary tumor cells to promote tumorigenesis. Recent evidence has shined a spotlight not only on the tumor cell itself, but the tumor microenvironment, or stroma, which surrounds the tumor. This is evidenced by Hanahan and Weinberg recently updating their landmark review of the hallmarks of cancer to include microenvironment specific components [11]. The microenvironment contains multiple resident and infiltrating cells, including immune cells, along with the growth factors and cytokines that they release. A supportive tumor microenvironment appears crucial for the development of a tumor as well as its transition to malignancy, and the characteristics of a pro-tumorigenic microenvironment has been well reviewed [12]. This review will focus on tumor evasion of immune surveillance, and how COX-2-derived PGE2 can modulate local immune responses in the tumor stroma to support progression and metastasis.
Section snippets
Metabolism and tumorigenic properties of PGE2
PGE2 makes up the majority of secreted prostaglandin in tumors and is thought to be the principal tumorigenic COX-2-derived product. This has been studied in a broad range of cancers, though perhaps most intensively in colorectal cancer [2]. PGE2 is generated through the conversion of PGH2 by microsomal PGE synthases (mPGES) 1 or 2, or cytosolic (c) PGES. Like COX-2, mPGES-1 is inducible and appears to be the dominant PGE2-generating enzyme in tumors [13]. Functional coupling of COX-2 and
COX-2 in breast cancer
Animal and human studies report COX-2 overexpression in breast cancer [4], [29], [30], [31], and strongly support a role for this enzyme in disease progression. Targeted overexpression of COX-2 gene in the mammary epithelium, via the mouse mammary tumor virus, was sufficient to induce mammary tumorigenesis in multiparous mice through a PGE2-EP2 pathway [32], [33]. Further studies in this model revealed an upregulation of cytochrome P450 aromatase that was reversed following COX-2 inhibition
Immune regulation of tumorigenesis
In the past decade, evidence has quickly mounted that genetic mutations in classical cancer signaling pathways of tumor epithelial cells cannot fully explain differences in phenotype and clinical development of tumors [42], [43]. Indeed, cancer is increasingly considered a disease of the tissue and its progression depends on the supportive or suppressive nature of the microenvironment in the surrounding stroma. The microenvironment contains several different cell types, including fibroblasts,
Effect of PGE2 on tumor-associated macrophages
Tumor-associated macrophages (TAM) represent the majority of tumor infiltrating leukocytes [46]. Macrophages are particularly relevant to the tumor microenvironment because, in addition to their role as modulators of angiogenesis, tumor cell migration, and matrix remodeling, they can support or suppress local immune responses thereby contributing to immune surveillance or escape. Macrophages express Toll-like receptors, mannose receptors, and scavenger receptors that can all activate classical
Effect of PGE2 on myeloid-derived suppressor cells
A growing appreciation for the role of MDSCs in tumor immunosuppression has developed over the past decade. Interest in MDSCs began in the 1980s when MDSCs were more commonly referred to as natural suppressor cells or bone marrow suppressor cells. MDSCs were originally identified as a subset of bone marrow cells that could inhibit T cell and NK proliferation that were characteristically distinguished from macrophages by their inability to adhere to nylon wool [64]. Since then, murine MDSCs have
Effect of PGE2 on T regulatory cells
A subset of CD4+ T cells that suppress effector T cell functions have a crucial role in preventing self (vs. non-self) destruction and thus are implicated in a variety of autoimmune diseases [77]. This same subset of T cells may be involved in T cell anergy in tumorigenesis and modify the immune response to accept the tumor as self instead of marking it for destruction. Classification, development, and function of these regulatory T cells (Tregs), which is still ill-defined and the subject of
Conclusion
The tumor immune microenvironment involves a remarkably complex interplay of cells and mediators that can drive a tumor towards limitless growth or imminent destruction. Multiple different cell types, and subtypes, exist in a milieu of growth factors, cytokines, oxidative species, and lipid mediators. Among these, PGE2 has emerged as a mediator that not only impacts classical oncogenic signaling pathways in tumor cells, but also contributes to shifting the tumor microenvironment towards immune
Acknowledgments
Part of the work described in this review was supported by a grant from the American Cancer Society (RSG-08-024-21 to E.M.S.). We acknowledge the technical assistance of Ms Victoire Ndong.
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2021, Toxicology ReportsCitation Excerpt :In breast cancer, COX2 could modulate growth, progression, invasion and even metastasis. The effect of PGE2 is mediated by activation of multiple mediators such as endothelial growth factor receptor (EGFR), extracellular-signal-regulated kinase (ERK) and metalloproteinase-9 (MMP9) [1–3]. PGE2 exerts its action through coupling with four E-Prostanoid receptors (EP), among them EP1 that plays a crucial role in hepatocellular carcinoma and was also expressed in other cancerous tissues including breast cancer [4].