The Role of Specialized Pro-Resolving Lipid Mediators in Inflammation-Induced Carcinogenesis

Abstract

Cancer is a process involving cell mutation, increased proliferation, invasion, and metastasis. Over the years, this condition has represented one of the most concerning health problems worldwide due to its significant morbidity and mortality. At present, the incidence of cancer continues to grow exponentially. Thus, it is imperative to open new avenues in cancer research to understand the molecular changes driving DNA transformation, cell-to-cell interaction derangements, and immune system surveillance decay. In this regard, evidence supports the relationship between chronic inflammation and cancer. In light of this, a group of bioactive lipids derived from polyunsaturated fatty acids (PUFAs) may have a position as novel anti-inflammatory molecules known as the specialized pro-resolving mediators (SPMs), a group of pro-resolutive inflammation agents that could improve the anti-tumor immunity. These molecules have the potential role of chemopreventive and therapeutic agents for various cancer types, and their effects have been documented in the scientific literature. Thus, this review objective centers around understanding the effect of SPMs on carcinogenesis and their potential therapeutic effect.

Keywords: bioactive lipids; cancer; carcinogenesis; chronic inflammation; polyunsaturated fatty acids; specialized pro-resolving lipid mediators.

Figure 1

Biosynthesis of SPMs and their actions in inflammation. (A) LX are generated from AA via 5, 12, 15-LOX, resulting in LXA4 and LXB4, whose receptor is ALX/FPR2. DHA, via COX-2/Aspirin as well as via 15-LOX, produces 17-HpDHA, which can be metabolized into PD1 or NPD1 and is synthesized in the nervous system or into 17-HDHA, generating RvD1-6 via 5-LOX, with activity on ALX or GPR32. Another DHA pathway is through 12-LOX, where MaR1-2 and MCTRs are produced. Finally, the biosynthesis of RvE1-3 derives from EPA, by the enzymes COX-2/Aspirin or CYP450, being their receptor CMKLR1. (B). SPMs in inflammation: the inflammatory microenvironment starts with PMN migration. Afterward, the change of pro-inflammatory LMs into pro-resolving ones occurs with the initial synthesis of LXs. PMN infiltration increases, and SPMs act at this point, reducing this influx. Moreover, the efferocytosis by MØ is stimulated and improved by Rvs, MaRs, and LXs. Adaptive immunity, stimulated by SPMs, participates during the final phase of resolution. However, whenever there is an exaggerated and chronic inflammatory response, it leads to chronic inflammation, inhibited by Rvs, and LXs. Abbreviations: SPMs: specialized pro-resolving mediator; AA: Arachidonic acid; LXs: Lipoxins; LOX: lipoxygenase; LXA4: lipoxin A4; LXB4: lipoxin B4; ALX: G protein-coupled lipoxin A4 receptor; formyl peptide receptor; DHA: docosahexaenoic acid; COX-2/Aspirin: Aspirin acetylates cyclooxygenase-2; 17-HpDHA: 17-hydroperoxyDHA; PD1: Protectin 1; NPD1: neuroprotectin 1; 17-HDHA: 17-hydroxy-DHA; Rvs: D1-6-series resolvins; GPR32: G protein-coupled receptor; MaRs1-2: Maresins 1-2; MCTR: maresin conjugates in tissue regeneration; RvE1-3: E1-3-series resolvins; EPA: Eicosapentaenoic acid; CYP450: cytochrome P450; CMKLR1: chemokine-like receptor 1; PMN: polymorphonuclear neutrophil; LM: lipid mediators; and MØ: macrophages.

Figure 2

Implications of chronic inflammation in cancer development. (1) In situations such as persistent infections, an immune response is triggered, and this leads to the release of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-8, inducing the chemotaxis of immune cells and the production of free radicals. When the inflammatory process becomes chronic, the reactive oxygen and nitrogen species are capable of damaging DNA. TNF-α activates the NF-KB pathway, generating free radicals and a Th1 response with certain anti-tumor properties. However, the activation of the STAT-3 pathway by IL-6 counteracts this effect, generating a Th2 response and inducing the production of IL-10. (2) The STAT-3 pathway stimulates neovascularization via the production of VEGF, as well as through the stimulation of the expansion of Th17 and Treg lymphocytes. These lymphocytes contribute to tumor growth and neovascularization via IL-17 and inhibit the mechanisms of anti-tumoral immunity. The Th2 response generates IL-10, pushing macrophages towards the M2 phenotype known for their pro-tumoral properties, such as the release of substances that favor tumor growth and survival. (3) At this point, tumor growth is stimulated by pro-inflammatory cytokines in the environment. Angiogenesis continues at the expense of VEGF, and cytokines, such as IL-10 and TGF-B, contribute to the processes of immune evasion, generating a state of tumor-induced immunosuppression. Abbreviations: TNF-α: tumor necrosis factor Alpha; IL-6: Interleukin 6; IL-8: Interleukin 8; IL-10: Interleukin 10; IL-17: Interleukin 17; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; Treg: Regulatory T Cell; VEGF: Vascular endothelial growth factor; TGF-β: Transforming growth factor beta; and MMP-2: matrix metalloproteinase-2.

Figure 3

Mechanisms of action involving SPMs in the modulation of the tumor microenvironment. SPMs display multimodal mechanisms of action over malignant neoplasms. On one hand, the binding of molecules, such as LXA4 and RvD1 to the FPRL1 receptor, can result in a decrease in angiogenic phenomena via VEGF inhibition (1 and 3). On the other hand, the interaction between LXA4 and macrophages may restore their anti-tumoral actions via their transition from the M1 towards the M2 phenotype (2). Similarly, RvD2 increases characteristics such as phagocytosis, infiltration, proliferation, and survival of M2, as well as simultaneous reduction of pro-inflammatory cytokines, such as MPC1, IL-6, TNF, and CXCL10, in several types of immune cells located in the TME (4). Additionally, LXA4 can exert inhibitory effects over pro-tumoral cells, such as Breg lymphocytes (5), and stimulant effects on anti-tumoral immune cells, such as Tregs and neutrophils, potentiating their antineoplastic activity (6) or increasing the levels of chemotaxis towards the tumor (7). Finally, both LXA4 and RvD1 directly lead to the decrease of essential pro-tumoral processes, such as invasion, metastasis, and EMT, by interacting with receptors located on the surface of cancer cells (8). Abbreviations: RvD2: Resolvin D2; RvD1: Resolvin D1; SPMs: Specialized Pro-Resolving Mediators; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin 6; MPC1: Mitochondrial Pyruvate Carrier 1; CXCL10: C-X-C Motif Chemokine 10; LXA4: Lipoxin 4; VEGF: Vascular Endothelial Growth Factor; FT3: Transcription Factor 3; ERK: Extracellular Signal-regulated Kinase; Breg cells: Regulatory B cells; FPRL1: Formyl Peptide Receptor-like 1; FPR2: Formyl Peptide Receptor 2; EMT: Epithelial Mesenchymal Transition; TGF-B1: Transforming Growth Factor Beta 1; COMP: Cartilage Oligomeric Matrix Protein; and FOXM1: Forkhead Box Protein M1.