Editing Inflammation (section)

=== Cancer ===
Inflammation orchestrates the [[Tumor microenvironment|microenvironment]] around tumours, contributing to proliferation, survival and migration.<ref>{{Cite journal |vauthors=Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R |date=September 2011 |title=Interaction of tumor cells with the microenvironment |journal=Cell Communication and Signaling |volume=9 |pages=18 |doi=10.1186/1478-811X-9-18 |pmc=3180438 |pmid=21914164 |doi-access=free}}</ref> Cancer cells use [[selectins]], [[chemokines]] and their receptors for invasion, migration and metastasis.<ref name="Coussens" /> On the other hand, many cells of the immune system contribute to [[cancer immunology]], suppressing cancer.<ref name="pmid22914051">{{Cite journal |vauthors=Gunn L, Ding C, Liu M, Ma Y, Qi C, Cai Y, Hu X, Aggarwal D, Zhang HG, Yan J |date=September 2012 |title=Opposing roles for complement component C5a in tumor progression and the tumor microenvironment |journal=Journal of Immunology |volume=189 |issue=6 |pages=2985–94 |doi=10.4049/jimmunol.1200846 |pmc=3436956 |pmid=22914051}}</ref>
Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as [[NF-κB]], may mediate some of the most critical effects of inflammatory stimuli on cancer cells.<ref name="pmid19382224">{{Cite journal |vauthors=Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA |date=June 2009 |title=Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? |journal=BioEssays |volume=31 |issue=6 |pages=629–41 |doi=10.1002/bies.200800138 |pmid=19382224 |s2cid=205469320}}</ref> This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells is very likely to affect carcinogenesis. On the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.

There is some evidence from 2009 to suggest that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.<ref name="pmid19468060">{{Cite journal |vauthors=Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A |date=July 2009 |title=Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability |journal=Carcinogenesis |type=review |volume=30 |issue=7 |pages=1073–81 |doi=10.1093/carcin/bgp127 |pmid=19468060 |doi-access=free}}</ref>{{Update needed|date=October 2024}}

====Role in cancer====

In 1863, [[Rudolf Virchow]] hypothesized that the origin of cancer was at sites of chronic inflammation.<ref name="Coussens">{{Cite journal |vauthors=Coussens LM, Werb Z |year=2002 |title=Inflammation and cancer |journal=Nature |volume=420 |issue=6917 |pages=860–7 |bibcode=2002Natur.420..860C |doi=10.1038/nature01322 |pmc=2803035 |pmid=12490959}}</ref><ref name="Chiba">{{Cite journal |vauthors=Chiba T, Marusawa H, Ushijima T |date=September 2012 |title=Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation |url=http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160134/1/j.gastro.2012.07.009.pdf |url-status=live |journal=Gastroenterology |volume=143 |issue=3 |pages=550–563 |doi=10.1053/j.gastro.2012.07.009 |pmid=22796521 |s2cid=206226588 |archive-url=https://web.archive.org/web/20220829232437/https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160134/1/j.gastro.2012.07.009.pdf |archive-date=29 August 2022 |access-date=9 June 2018 |hdl-access=free |hdl=2433/160134}}</ref> As of 2012, chronic inflammation was estimated to contribute to approximately 15% to 25% of human cancers.<ref name="Chiba" /><ref name="pmid18650914">{{Cite journal |vauthors=Mantovani A, Allavena P, Sica A, Balkwill F |date=July 2008 |title=Cancer-related inflammation |url=https://air.unimi.it/bitstream/2434/145688/2/Cancer-related%20inflammation_Nature.pdf |url-status=live |journal=Nature |volume=454 |issue=7203 |pages=436–44 |bibcode=2008Natur.454..436M |doi=10.1038/nature07205 |pmid=18650914 |s2cid=4429118 |archive-url=https://web.archive.org/web/20221030195610/https://air.unimi.it/bitstream/2434/145688/2/Cancer-related%20inflammation_Nature.pdf |archive-date=30 October 2022 |access-date=9 June 2018 |hdl-access=free |hdl=2434/145688}}</ref>

====Mediators and DNA damage in cancer====

An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response.<ref name="pmid6399978">{{Cite journal |vauthors=Larsen GL, Henson PM |year=1983 |title=Mediators of inflammation |journal=Annual Review of Immunology |volume=1 |pages=335–59 |doi=10.1146/annurev.iy.01.040183.002003 |pmid=6399978}}</ref> Inflammatory mediators that contribute to neoplasia include [[prostaglandin]]s, inflammatory [[cytokine]]s such as [[Interleukin 1 beta|IL-1β]], [[tumor necrosis factor alpha|TNF-α]], [[Interleukin 6|IL-6]] and [[Interleukin 15|IL-15]] and [[chemokine]]s such as [[Interleukin 8|IL-8]] and [[CXCL1|GRO-alpha]].<ref name="Shacter">{{Cite journal |vauthors=Shacter E, Weitzman SA |date=February 2002 |title=Chronic inflammation and cancer |journal=Oncology |volume=16 |issue=2 |pages=217–26, 229; discussion 230–2 |pmid=11866137}}</ref><ref name="Chiba" /> These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival.<ref name="Coussens" /><ref name="Shacter" />

Inflammation also causes DNA damages due to the induction of [[reactive oxygen species]] (ROS) by various intracellular inflammatory mediators.<ref name="Coussens" /><ref name="Shacter" /><ref name="Chiba" /> In addition, [[White blood cell|leukocytes]] and other [[Phagocyte|phagocytic cells]] attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS and [[reactive nitrogen species]] (RNS). ROS and RNS are normally produced by these cells to fight infection.<ref name="Coussens" /> ROS, alone, cause more than 20 types of DNA damage.<ref name="pmid27989142">{{Cite journal |vauthors=Yu Y, Cui Y, Niedernhofer LJ, Wang Y |date=December 2016 |title=Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage |journal=Chemical Research in Toxicology |volume=29 |issue=12 |pages=2008–2039 |doi=10.1021/acs.chemrestox.6b00265 |pmc=5614522 |pmid=27989142}}</ref> Oxidative DNA damages cause both [[mutation]]s<ref name="pmid22293091">{{Cite journal |vauthors=Dizdaroglu M |date=December 2012 |title=Oxidatively induced DNA damage: mechanisms, repair and disease |journal=Cancer Letters |volume=327 |issue=1–2 |pages=26–47 |doi=10.1016/j.canlet.2012.01.016 |pmid=22293091}}</ref> and epigenetic alterations.<ref name="pmid24281019">{{Cite journal |vauthors=Nishida N, Kudo M |year=2013 |title=Oxidative stress and epigenetic instability in human hepatocarcinogenesis |journal=Digestive Diseases |volume=31 |issue=5–6 |pages=447–53 |doi=10.1159/000355243 |pmid=24281019 |doi-access=free}}</ref><ref name="Chiba" /><ref name="Ding">{{Cite journal |vauthors=Ding N, Maiuri AR, O'Hagan HM |year=2017 |title=The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases |journal=Mutation Research |volume=780 |pages=69–81 |doi=10.1016/j.mrrev.2017.09.005 |pmc=6690501 |pmid=31395351}}</ref> RNS also cause mutagenic DNA damages.<ref name="pmid28050219">{{Cite journal |vauthors=Kawanishi S, Ohnishi S, Ma N, Hiraku Y, Oikawa S, Murata M |year=2016 |title=Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells |journal=Genes and Environment |volume=38 |issue=1 |pages=26 |bibcode=2016GeneE..38...26K |doi=10.1186/s41021-016-0055-7 |pmc=5203929 |pmid=28050219 |doi-access=free}}</ref>

A normal cell may undergo [[carcinogenesis]] to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic [[mutation]]s due to [[DNA repair#Translecion synthesis|inaccurate repair]]. In addition, mistakes in the DNA repair process may cause [[Cancer epigenetics|epigenetic]] alterations.<ref name="Chiba" /><ref name="Shacter" /><ref name="Ding" /> Mutations and epigenetic alterations that are replicated and provide a selective advantage during somatic cell proliferation may be carcinogenic.

Genome-wide analyses of human cancer tissues reveal that a single typical cancer cell may possess roughly 100 mutations in [[coding region]]s, 10–20 of which are [[carcinogenesis|"driver mutations"]] that contribute to cancer development.<ref name="Chiba" /> However, chronic inflammation also causes epigenetic changes such as [[DNA methylation in cancer|DNA methylation]]s, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (see [[DNA methylation in cancer]]). Sites of oxidative damage in [[chromatin]] can recruit complexes that contain [[DNA methyltransferase]]s (DNMTs), a histone deacetylase ([[sirtuin 1|SIRT1]]), and a [[EZH2|histone methyltransferase (EZH2)]], and thus induce DNA methylation.<ref name="Chiba" /><ref name="pmid22094255">{{Cite journal |vauthors=O'Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL, Baylin SB |date=November 2011 |title=Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands |journal=Cancer Cell |volume=20 |issue=5 |pages=606–19 |doi=10.1016/j.ccr.2011.09.012 |pmc=3220885 |pmid=22094255}}</ref><ref name="pmid28522752">{{Cite journal |vauthors=Maiuri AR, Peng M, Podicheti R, Sriramkumar S, Kamplain CM, Rusch DB, DeStefano Shields CE, Sears CL, O'Hagan HM |date=July 2017 |title=Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis |journal=Cancer Research |volume=77 |issue=13 |pages=3467–3478 |doi=10.1158/0008-5472.CAN-17-0056 |pmc=5516887 |pmid=28522752}}</ref> DNA methylation of a [[CpG site|CpG island]] in a [[Promoter (genetics)|promoter region]] may cause silencing of its downstream gene (see [[CpG site]] and [[regulation of transcription in cancer]]). DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (see [[DNA methylation in cancer#Likely role of hypermethylation of DNA repair genes in cancer|hypermethylation of DNA repair genes in cancer]]). A 2018 report<ref name="pmid29358395">{{Cite journal |vauthors=Yamashita S, Kishino T, Takahashi T, Shimazu T, Charvat H, Kakugawa Y, Nakajima T, Lee YC, Iida N, Maeda M, Hattori N, Takeshima H, Nagano R, Oda I, Tsugane S, Wu MS, Ushijima T |date=February 2018 |title=Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=6 |pages=1328–1333 |bibcode=2018PNAS..115.1328Y |doi=10.1073/pnas.1717340115 |pmc=5819434 |pmid=29358395 |doi-access=free}}</ref> evaluated the relative importance of mutations and epigenetic alterations in progression to two different types of cancer. This report showed that epigenetic alterations were much more important than mutations in generating gastric cancers (associated with inflammation).<ref name="pmid24664859">{{Cite journal |vauthors=Raza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, Khan S, Kazi JI, Bernstein C, Kazmi SU |date=October 2014 |title=Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis |journal=Pathology & Oncology Research |volume=20 |issue=4 |pages=839–46 |doi=10.1007/s12253-014-9762-1 |pmid=24664859 |s2cid=18727504}}</ref> However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated with [[Cigarette#Smokers|tobacco chemicals]] and [[Acetaldehyde#Carcinogenicity|acetaldehyde]], a product of alcohol metabolism).