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Inflammation and cancer
Different types of inflammation contribute to tumour development in different ways; chronic
inflammation leads to mutations, genomic instability, angiogenesis and tumour development;
tumour associated inflammation leads to genomic instability, angiogenesis,
immunosuppression, metastasis and tumour growth; inflammation caused by environmental
exposure leads to mutations, genomic instability, angiogenesis and tumour promotion;
therapy induced inflammation leads to antigen presentation
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Cancer-enabling inflammation
Infiltrating cancers provoke a chronic inflammatory reaction, causing systemic signs and
symptoms such as anaemia, fatigue, and cachexia
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Cancer enabling effects of inflammatory cells- Release of factors that promote proliferation
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- Removal of growth suppressors
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- Enhanced resistance to cell death
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Tumour-associated macrophages prevent anokis by expressing adhesion
molecules such as integrins that promote direct physical interactions with tumour
cells
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- Inducing angiogenesis
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- Activating invasion and metastasis
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Other factors released by stromal cells, such as
TGF-beta, may promote epithelial-mesenchymal transitions, a key event in the
process of invasion and metastasis
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A variety of soluble factors released by macrophages
and other stromal cells contribute to the immunosuppressive T regulatory cells or
suppress the function of CD8+ cytotoxic T cells
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- Inhibition of tumor growth by antigen presentation, cytokines and reactive
oxygen/nitrogen intermediates
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Paracrine regulation of inflammatory pathways
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Upregulation of the inflammatory mediator cyclooxygenase-2 (COX-2)
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Promotion of tumour growth by regulatory T cells that suppress antitumor T cell
responses
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Evidence that inflammation promotes cancer
- Many inflammatory conditions predispose to cancer
- Cancers arise at sites of chronic inflammation
- Functional polymorphisms of cytokine genes are associated with cancer
- Distinct populations of inflammatory cells are detected in many types of cancer
- Extent of tumour associated macrophage infiltration correlates with prognosis
- Inflammatory cytokines are detected in many cancers
- Deletion of cytokine and chemokine genes protects against carcinogens, as
evidenced in knockout gene murine experiments
- Inflammatory cytokines are implicated in the action of non-genotoxic liver
carcinogens
- The inflammatory cytokine TNF is directly transforming in vitro
- The long term use of nonsteroidal anti-inflammatory drugs decreases mortality from
colorectal cancer
- Selective COX-2 inhibitors reduce cancer incidence
- Polymorphisms in genes that regulate immune balance influence cancer risk
- In cancers, an abundance of infiltrating innate immune cells, such as macrophages,
mast cells, and neutrophils, correlates with increased angiogenesis and/or poor
prognosis
- In cancers, an abundance of infiltrating lymphocytes correlates with favourable
prognosis
Inflammation dependent tumour promotion
In a mouse tumour model, liver carcinogenesis was provoked through deletion of the mdr
(multidrug-resistance) gene in the mouse germ line, loss of this gene and its encoded
product leads to accumulation of bile acids in the liver and resulting chronic liver
inflammation
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in the liver of these
mice, TNF-alpha is initially produced by inflamed endothelial cells as well as infiltrating
immune cells in the stroma, such as neutrophils and macrophages
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The TNF- receptors respond by activating IKK, which induces NK-KB signalling, which drives
expression of anti-apoptotic genes (eg
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cyclin D1 encoding
genes), and the gene encoding TNF-alpha, expression of additional TNF-alpha leads to
amplification of the inflammatory response
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This

progression can be blocked by antibodies reactive with TNF-alpha as well as a
dominant-negative, biodegradable IKB
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Chronic inflammation plays a role in the pathogenesis of human carcinomas
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HBV may create liver cancer through its ability to
cause continuous cell proliferation in an organ that normally experiences very little, this
proliferation is required to replace hepatocytes that are continually being killed by HBV
infectious cycles
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Chronic hepatitis C virus infections act in a similar way to increase liver cancer rates
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Loss-of-function mutations in the genes encoding IL-10 and the IL-10 receptor are
associated with very early onset IBD cytokines not only drive intestinal inflammation and
diarrhoea in IBD but may also regulate extra-intestinal disease manifestations and systemic
effects
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Proinflammatory cytokines IL-6, IL-12,
IL-23 and IL-21, antiinflammatory cytokines IL-10, and transforming growth factor -beta have
been identified as potential targets for the therapy of intestinal inflammation
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new approaches for anti-cytokine therapy in IBD patients may include multi-cytokine
blockers, such as tofacitinib

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