Download Week 8--2/29

Inflammation & Cancer
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Chronic Inflammation
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Ulcerative Colitis
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Why would chronic inflammation lead to cancer?
• The pathogen (e.g., virus) carries an oncogene that is
inappropriately expressed.
• Infection leads to cell death that requires rapid proliferation that
is associated with an accumulation of replication-induced
mutations.
• In its effort to clear the infectious agent, the immune system
causes some undesirable side-effects.
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Inactive Trypsin
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Why would chronic inflammation lead to cancer?
• The pathogen (e.g., virus) carries an oncogene that is
inappropriately expressed.
• Not all chronic inflammation is due to an infectious agent. For
those that are, no oncogenes have been identified.
• Infection leads to cell death that requires rapid proliferation that
is associated with an accumulation of replication-induced
mutations.
• The rate of replication-induced mutations is 1:109, assuming the
repair mechanisms are working properly.
• In its effort to clear the infectious agent, the immune system
causes some undesirable side-effects.
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NSAID Use
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75 mg aspirin/day for 10 years
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Mouse Models
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Target Genes of NF-kB
Cytokines/Chemokines and their Modulators
Immunoreceptors
Proteins Involved in Antigen Presentation
Cell Adhesion Molecules
Acute Phase Proteins
Stress Response Genes
Cell Surface Receptors
(-) Regulators of Apoptosis
Growth Factors, Ligands and their Modulators
Early Response Genes
Transcription Factors
Enzymes
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Autocrine signaling
Autocrine signaling through PGE2
cox2
ROS/RNS?
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Paracrine signaling
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Autocrine signaling
Autocrine signaling through PGE2
cox2
NSAIDs
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Paracrine signaling
MAPKKK Pathway
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TumorInfiltrating
Lymphocytes
(TILs)
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Macrophages
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TumorAssociated
Macrophages
(TAMs)
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- -
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CSF-1 = M-CSF
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- -
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CSF-1
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CSF-1 - -
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CSF-1/M-CSF
MCP-1/CCL2
RANTES/CCL5
VEGF
PDGF
CSF-1
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MIP-1g
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TNF-a
Growth
Survival
More inflammatory cells
COX-2/PGE2
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Matrix Metalloproteinases
(MMPs)
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- -
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Lack paracrine support
Hydrodynamic sheer forces
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