BMS3021 Lecture Notes - Lecture 23: Gastric Mucosa, Gastritis, Serology
30 May 2018
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Week 9. The inflammatory network in cancer and,
How do microbes (bugs) cause chronic inflammation
and cancer
THE INFLAMMATORY NETWORK IN CANCER
• Inflammation:
4 signs:
1. Pain
2. Redness
3. Heat
4. Swelling – caused by changed in blood vessels
• Acute vs Chronic:
Acute inflammation
Chronic inflammation
o Response of the body to harmful stimuli
eg. bacteria, viruses
o Characterised by increased movement of
plasma and leukocytes from the blood into
the injured tissues
o Results in removal of pathogens by
phagocytosis, blood vessel formation and
tissue regeneration
o Prolonged inflammation
o Eg. Hep B and C
o Leads to progressive shift in the type of cells
which are present at the site of inflammation
eg. chemokines will cause transformation of
cells
o Characterised by simultaneous destruction
and healing of the tissue from the
inflammatory process (wound that never
heals)
• Key inflammatory mediators:
(leukocytes, cytokines, chemokines, GF, TF (NFkB, STAT3))
o Leukocytes:
WBC
Lymphocytes
Neutrophils
Macrophages
Eosinophils and basophils
o Cytokines :
Secreted proteins
Cell signalling molecules that mediate cell to cell communication in immune
responses
Secreted by carious cell types: epithelial cells, endothelial cells and macrophages
Circulate in very low concentration under normal conditions
In response to inflammation their expression and/or secretion can increase
induction by up to a thousand fold
find more resources at oneclass.com
find more resources at oneclass.com
o Chemokines:
Sublass of cytokine
Eg. IL-8
Different chemokines can stimulate movement of specific leukocyte populations
towards sites of inflammation (chemoattraction)
Leukocytes express chemokine receptors for responding to chemokines
o Growth factors (GF):
Large family of cytokines
Stimulate cell growth, proliferation and differentiation
Eg. TNF (tumour necrosis factor), CSF, EGF
• Evidence that links cancer and inflammation:
-inflammation is seen in almost all tumours and has very strong evidence
1. Inflammatory diseases increase the risk of developing cancer
eg. Helicobacter Pylori and gastric cancer
2. Non-steroidal anti-inflammatory – drugs that reduce the risk of developing certain
cancers (eg. colon and breast cancer by inhibiting inflammation)
3. Signalling pathways involved in inflammation operate downstream of oncogenic
mutations
4. Inflammatory cells, chemokines and cytokines are present in the microenvironment of
all tumours in experimental animal models and humans
5. Targeting of inflammatory mediators (chemokines, cytokines eg. TNF-a and IL-1B) and
key transcriptional factors (eg. STAT3) decreases the incidence and spread of cancer
-inhibiting these mediators = links to decrease in spread of cancer
-drugs that target these also reduce some tumorigenic effect
6. Overexpression of inflammatory cytokines promotes the development of tumours
• Pathways that link chronic inflammation to cancer:
I. Intrinsic pathway
Activated by genetic events that cause neoplasia
(cancer)
-includes activation of various types of oncogenes (eg.
ras) by mutation, chromosomal rearrangement or
amplification and the inactivation of tumour-suppressor
genes
Transformed cells (tumour cells) produce inflammatory
mediators -> generate inflammatory microenvironment
in tumours (eg. breast tumours)
Once activated can upregulate chemokines and TF
Eg. activation of the oncogene (eg. ras) and the Ras-Raf
signalling pathway – can result in activation of TF
-stimulates proliferation of tumour cells
-induces the production of tumour promoting
inflammatory chemokines and cytokines
find more resources at oneclass.com
find more resources at oneclass.com
II. Extrinsic pathway
Triggered by inflammation or infections
eg. inflammation by bacteria
Induces production of inflammatory mediators
(cytokines/chemokines which in turn can activate TF in
tumour cells)
Augments the risk of developing cancer at certain
anatomical sites (eg. colon, stomach, prostate)
Eg. Infection with helicobacter pylori
gastric ulcer -> gastric cancer
III. Development of a cancer-related
inflammatory microenvironment
Chemokines produced by tumour cells recruit
inflammatory cells
Intrinsic and extrinsic pathways converge
Cytokines secreted by inflammatory cells activate TF
(eg. NFkB), signal transducer and activator of
transcription 3 (STAT3) in tumour, inflammatory and
stromal cells
TF’s atiate production of more inflammatory
mediators plus survive factors
Eg. in pancreatic cancer both pancreatitis (extrinsic)
and mutations in gene encoding K-Ras (intrinsic) are
frequently found
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
How do microbes (bugs) cause chronic inflammation and cancer. 4 signs: pain, redness, heat, swelling caused by changed in blood vessels, acute vs chronic: Cell signalling molecules that mediate cell to cell communication in immune responses. Secreted by carious cell types: epithelial cells, endothelial cells and macrophages. Circulate in very low concentration under normal conditions. In response to inflammation their expression and/or secretion can increase induction by up to a thousand fold: chemokines: Different chemokines can stimulate movement of specific leukocyte populations towards sites of inflammation (chemoattraction) Leukocytes express chemokine receptors for responding to chemokines: growth factors (gf): Stimulate cell growth, proliferation and differentiation: evidence that links cancer and inflammation: Inflammation is seen in almost all tumours and has very strong evidence. Inhibiting these mediators = links to decrease in spread of cancer. Drugs that target these also reduce some tumorigenic effect: overexpression of inflammatory cytokines promotes the development of tumours, pathways that link chronic inflammation to cancer, intrinsic pathway.
