Eicosanoids in carcinogenesis

Abstract

Inflammation is the body's reaction to pathogenic (biological or chemical) stimuli and covers a burgeoning list of compounds and pathways that act in concert to maintain the health of the organism. Eicosanoids and related fatty acid derivatives can be formed from arachidonic acid and other polyenoic fatty acids via the cyclooxygenase and lipoxygenase pathways generating a variety of pro- and anti-inflammatory mediators, such as prostaglandins, leukotrienes, lipoxins, resolvins and others. The cytochrome P450 pathway leads to the formation of hydroxy fatty acids, such as 20-hydroxyeicosatetraenoic acid, and epoxy eicosanoids. Free radical reactions induced by reactive oxygen and/or nitrogen free radical species lead to oxygenated lipids such as isoprostanes or isolevuglandins which also exhibit pro-inflammatory activities. Eicosanoids and their metabolites play fundamental endocrine, autocrine and paracrine roles in both physiological and pathological signaling in various diseases. These molecules induce various unsaturated fatty acid dependent signaling pathways that influence crosstalk, alter cell–cell interactions, and result in a wide spectrum of cellular dysfunctions including those of the tissue microenvironment. Although the complete role of eicosanoids, including that of the recently elucidated anti-inflammatory specialized pro-resolving lipid mediators (SPMs), e.g. lipoxins, resolvins, protectins and maresins, is not completely understood, the result of unremitting chronic inflammation is fostering early stages of carcinogenesis. Chronic inflammation facilitates the transition from a normal cell to a cancerous one. The disruption of homeostasis across a wide, but identifiable, swath of diverse molecular pathways creates a micromilieu which constitutes an early and necessary step in the 6-step sequence of carcinogenesis for the vast majority of cancers, termed “sporadic cancers”.

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

“…Ongoing pathogenic stimuli induces chronic inflammation [290,292], promotes fibrosis with its remodeled version, the PCN. Thus, the PCN explains why it is not just external stimuli that brings about carcinogenesis but the response of the host tissue [293] to such stimuli and the ability or inability of the host to interdict the pro-inflammatory pathways, signaling cascades [290,292], and fibrotic changes that describe the dysregulation of the cellular and tissue equilibrium (Fig. 1) which are, in toto, critical to carcinogenesis and, perhaps, equally important to the onset of metastasis.…”

Microbiome and morbid obesity increase pathogenic stimulus diversity

“…The microbial ecology has huge impact on life, evolution, as well as pathogenic stimuli on the development on cancer. The interplay of pathogenic stimuli with consequent chronic inflammation [8,9], proteins [177], and the release of cytokines from many cell types provide a micromilieu promoting the PCN (Fig. 1).…”

“…The microbiome with its diversity influences our life and often serves as pathogenic stimuli initiating chronic inflammation [8]. The diversity of the microbiome can result in a dysbiosis triggering a disruption of homeostasis of pro-and anti-inflammatory mediators [9]. Of course, the importance of oral hygiene is well known to be associated with periodontitis, oral plaques, etc.…”

“…The interactions between the microbiome and morbid obesity are important to understand signaling and crosstalk in the context of carcinogenesis. This disruption of homeostasis increases remodeling of the extracellular matrix and fibrosis followed by the none-resolvable precancerous niche (PCN) as the internal pathogenic stimuli with pro-inflammatory mediators ensues [9]. The chronic stress response by the body explains why there is a greater proclivity for normal cells to undergo the transition to cancer cells.…”

Metformin alters signaling induced crosstalk and homeostasis in the carcinogenesis paradigm “Epistemology of the origin of cancer”

“…The detailed signaling and crosstalk resulting from a pathogenic stimulus and which evokes the chronic inflammation involved in morbid obesity had been reviewed earlier (reviewed in [13,67]). This is of significance in neurological diseases such as Parkinson or dementia as well (reviewed in [142]). Metformin is increasingly becoming recognized for decreasing the inflammasome.…”