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

2019

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A pathogenic (biological or chemical) stimulus is the earliest information received by a cell that can result in the disruption of homeostasis with consequent development of disease. Chronic inflammation involves many cell types with numerous cytokines and signaling pathways, the release of different components by the cells, and the crosstalk provoked by such stimuli involving subclinical chronic inflammation and is mechanistically manifold. Exosomes secrete chemicals that trigger the epithelium to produce exosome-like nanoparticles promoting chronic inflammation. Small molecules, together with various cytokines, selectively target signaling pathways inducing crosstalk that suppress apoptosis. 16S rRNA gene sequencing has become routine to provide information on the composition and abundance of bacteria found in human tissues and in reservoirs. The deregulation of autophagy with chronic stimulation of inflammation is an early phenomenon in carcinogenesis. The disruption of cell–cell integrity enables transcellular CagA migration and triggers deregulation of autophagy with the net result being chronic inflammation. The complex and insidious nature of chronic inflammation can be seen both inside and outside the cell and even with intracellular nuclear fragments such as chromatin, which itself can elicit a chronic inflammatory response within the cytoplasm and affect autophagy. The ultimate result of unresolved chronic inflammation is fibrosis, a step before tissue remodeling results in the formation of a precancerous niche (PCN). Various pathogenic stimuli associated with different neoplasms result in persistent inflammation. This ongoing disruption of homeostasis in the micromilieu of cells, tissues, and organs is an essential preamble to carcinogenesis and occurs early in that process.

Section: Discussionmentioning

confidence: 99%

“…The association of Helicobacter pylori and gastric cancer [138] was long ignored [139]. Eventually, the pathogen was shown to cause fibrosis, one step in the proposed six-step sequence of carcinogenesis [18].…”

Section: Pathogenic Stimulus By Bacteriamentioning

confidence: 99%

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

2019

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“…1). The complexity of dysregulated homeostasis increases when one considers the microbiome, high-fat diet, and morbid obesity [178]. The microbial flora itself can increase obesity.…”

Section: Discussionmentioning

confidence: 99%

Microbiome and morbid obesity increase pathogenic stimulus diversity

2019

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The microbiome, the relationship between environmental factors, a high-fat diet, morbid obesity, and host response have been associated with cancer, only a small fraction of which (<10%) are genetically triggered. This nongenetic association is underpinned by a worldwide increase in morbid obesity, which is associated with both insulin resistance and chronic inflammation. The connection of the microbiome and morbid obesity is reinforced by an approximate shift of about 47% in the estimated total number of bacteria and an increase from 38,000,000,000,000 in a reference man to 56,000,000,000,000 in morbid obesity leading to a disruption of the microbial ecology within the gut. Humans contain 6,000,000,000 microbes and more than 90% of the cells of the human body are microorganisms. Changes in the microflora of the gut are associated with the polarization of ion channels by butyrate, thereby influencing cell growth. The decrease in the relative proportion of Bacteroidetes together with a change in the fermentation of carbohydrates by bacteria is observed in morbid obesity. The disruption of homeostasis of the microflora in the obese changes signaling and crosstalk of several pathways, resulting in inflammation while suppressing apoptosis. The interactions between the microbiome and morbid obesity are important to understand signaling and crosstalk in the context of the progression of the six-step sequence of carcinogenesis. This disruption of homeostasis increases remodeling of the extracellular matrix and fibrosis followed by the none-resolvable precancerous niche as the internal pathogenic stimuli continue. The chronic stress explains why under such circumstances there is a greater proclivity for normal cells to undergo the transition to cancer cells.

“…Furthermore, important consequences of homeostasis disruption influencing the preparation of the precancerous niche (PCN) in this Special Issue "Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer" include undervalued ubiquitous proteins [464], various pathogenic stimulus evoking chronic inflammation [465], remodeled fibrosis by chronic inflammation [466], the microbiome and morbi obesity [467] and PCN induced chronic cellmatrix stress with normal to cancer cell transition [468].…”

Section: Summary (Fig 4)mentioning

confidence: 99%

Eicosanoids in carcinogenesis

2019

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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”.