Increase, Inflammation

Inflammation is complex to define. 

Villeneuve et al. (2018) analyzed the varied biological responses, provided guidance to simplify the  process representing inflammation in adverse outcome pathways, and recommended 3 key steps: 1. Tissue resident cell activation 2. Increased Pro-inflammatory mediators 3. Leukocyte recruitment/activation.  Tissue resident cell activation generally occurs when healthy tissue is exposed to a stressor, or when damage occurs, initiating a signal response of pro-inflammatory mediators (ex. cytokines).  Pro-inflammatory mediators result in the production of lipids and proteins, signaling, and initiate leukocyte recruitment/activation.  Leukocyte recruitment/activation initiate inflammation and other morphological changes. 

In cancer, inflammation is a cascade of events created by the host in response to the spread of the cancer (Coussens and Werb, 2002). In response to an injury or the presence of cancer, the host heals itself through inflammation. Indeed, the activation and the migration of  leukocytes (neutrophils, monocytes and eosinophils) to the wound induces the healing process. These inflammatory cells provide an extracellular matrix that forms upon which fibroblast and endothelial cells proliferate and migrate in order to recreate a normal environment. Damage to the epithelial layer initiate inflammatory reactions (Palmer et al. 2011).  In cancer, this inflammatory state induces cell proliferation, increases the production of reactive oxygen species leading to oxidative DNA damage, and reduces DNA repair (Coussens and Werb, 2002).  For review of inflammation caused by microplastics in mammals, see Wright and Kelly (2017).

Inflammation can be defined as the response of the organism to a tissue injury (Coussens). Indeed, in order to heal this injury, a multitude of chemical signals initiate and maintain a host response. Leukocytes (neutrophils, monocytes and eosinophils) are recruited to the site of the damage through the attraction by chemokines (TNF-α (tumour necrosis factor-α), interleukines…). A provisional extracellular matrix (ECM) is created, and fibroblast and endothelial cells proliferate and migrate to it. Wound healing is an example of physiological inflammation and is self-limiting (Coussens). In case of a dysregulation, inflammation can lead to pathologies. Inflammation can be caused by physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma (Singh).

Inflammation was described as one of the hallmarks of cancer by Hannahan et al. as a response to tumor invasion through mainly two mechanisms: promoting genetic instatbility and supply pro-tumorogenic factors.

First, inflammation in cancer promotes genetic instability (Mantovani, colotta). Macrophages, in contact with the inflammatory site can be responsible of a reactive stress oxygen reaction (ROS) (Maeda, Pollard, Grivennikov). Indeed, they generate high levels of reactive oxygen and nitrogen species which produce mutagenic agents (peroxynitrite), which in turn causes DNA mutations.

Second, in inflammation, the tumor micro environment plays a critical role (Coussens). Indeed, in can supply growth factors, survival factors, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis, and inductive signals that lead to activation of EMT and other hallmark-facilitating programs (Hannahan). For example, macrophages can become tumor associated macrophage which promote cell proliferation, angiogenesis, and invasion (Singh, Lin, Qian).

Moreover, chronic inflammation can also lead to tumorigenesis (Karin, Singh). Indeed, since 1863, Virchow has hypothesized that chronic inflammation causes cell proliferation (Balkwill). According to Aggarwall, several pro-inflammatory markers such as TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX mediate suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis (Aggarwal).

Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).  Activation of the innate immune response and the release of various inflammatory cytokines can also be assessed (Flake and Morgan, 2017).

Several assays can be used to measure inflammation:

• Histopathology on samples. Several scoring tools exist (Goeboes)
• Measuring chemokines in the blood (ELISA, multiplex bead assays : interleukines (IL1, IL6), TNF, interferon… ) (Brenner) and histopathology samples
• Measuring Prostaglandin levels, COX-2 (ELISA Liquid chromatography/tandem mass spectrometry, IHC)
• Transcription factors : STAT3 Activation, NF-κB Activation (ELISA RtPCR to measure mRNA
• Biomarkers (white cell count, CRP) ratios, and predictive score using
• Measuring ROS(DCFDA, horseradish peroxidase (HRP)-oxidizing substrates, SOD-inhibitable reduction of cytochrome c) (Murphy).

Methods are extensively reviewed in Marchand et al and Murphy et al.

Taxonomic: appears to be present broadly, with representative studies focused on mammals (humans, lab mice, lab rats).

Extensive data exists on the presence of inflammation in human (Coussens, Aggarwal, Hannhan, Mantovani..) In human, many examples of chronic inflammation leading to cancer or cancer progression exist. For instance, Helicobacter pylori infection leads to gut cancer (Wang).

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