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Inflammation and Inflammation and CancerCancer
Pin Ling ( 凌 斌 ), Ph.D. ext 5632; [email protected]
References: 1. “Hallmarks of Cancer: The Next Generation” (Cell,
2011) 2. “Paradoxical roles of immune system during cancer
development” (Nat Rev. Cancer, 2006)3. Insight Review on Inflammation (Nature, 2008, July)
Outline
1. Roles of the immune system in cancer development
2. Overview of Inflammation
3. Inflammation, The NF-kB pathway, and Cancer Development
4. Tumor microenvironment and Tumor-Associated Macrophages
Cancer development & Microenvironment1. Cancers are not only autonomous masses of mutant
cells.=> Composed of other cell types?=> fibroblasts, epithelial cells, “immune cells”, cells forming blood & lymphatic vessels, & mesenchymal cells.
2. “Tissue homeostasis” is maintained by coordinated interactions between these diverse cell types.=> How about cancer? => Cancerous cells hijack the normal physiological
process to favour their own survival.
3. Most cancers found in clinical are already the outcome of hijacking microenvironment by malignant cells
Here we focus on the relationship between the immune cells and cancers.
Paradoxical roles of the immune system in cancer
development1. The key functions of the mammalian immune
system: (1) Protect from infectious pathogens(2) Monitor tissue homeostasis => Eliminate damaged
cells or tumor cells
2. Mechanisms against cancer development: (1) Cellular immunity- T, NK, & Other innate immune cells(2) Humoral immunity- Cytokines, Abs, ..etc
3. Mechanisms promoting cancer development: (1) Inflammation => Angiogenesis & Tissue remodelling(2) Enhance survival pathways (NF-kB)(3) Suppression of anti-tumor immune responses
Cancers display the signs of inflammation
-infiltration of immune cells
HE Stain
CD45 Stain (all immune cells)
Most cancers outplay the immune system
=> Escape from cytotoxic T cell attacks=> Make other immune cells help their survival
The complex relationship between the immune system
and cancers-I1. Adaptive and innate immune cells regulate tissue
homeostasis and efficient wound healing
2. Altered interactions between adaptive and innate immune cells can lead to “chronic inflammatory disorders”.
3. Chronic inflammatory conditions enhance a predisposition to cancer development.
4. In cancers, an abundance of infiltrating innate immune cells (e.g. macrophages, mast cells, and neutrophils) correlates with increased angiogenesis and/or poor prognosis.
The complex relationship between the immune system
and cancers-II5. Long-term usage of non-steroidal anti-inflammatory
drugs and selective cyclooxygenase 2 (COX2) inhibitors reduces cancer incidence.
6. In cancers, an abundance of infiltrating lymphocytes correlates with favourable prognosis.
7. Activation of anti-tumour adaptive immune responses can suppress tumour growth
8. Polymorphisms in genes that regulate immune balance influence cancer risk.
9. Genetic elimination or depletion of immune cells alters cancer progression in experimental models.
Outline
1. Roles of the immune system in cancer development
2. Overview of Inflammation
3. Inflammation, The NF-kB pathway, and Cancer Development
4. Tumor microenvironment and Tumor-Associated Macrophages
Key Concepts about Inflammation-I
1. Inflammation- A physiological process whereby tissues respond to infectious & non-infectious insults (also called sterile inflammation, including toxic, traumatic, or autoimmune insults).
2. Four key signs: (1) Redness (2)Swelling (3) Heat (4)Pain
3. This process includes several phases: (1) Initial phase-Changes in local blood flow &
accumulation of inflammatory cells (neutrophiles, macrophages, DCs, & lymphocytes)(2) Middle phase-Resolution of initial insults(3) Final phase-Termination of inflammation & tissue
repair
Causes & Outcomes of Causes & Outcomes of InflammationInflammation
The Inflammatory Pathway
Inflammation in innate and adaptive immunity
Inflammatory cells, cytokines, & chemokines are major effectors in this process.
PRRs for sensing infectious & PRRs for sensing infectious & endogenous stimuliendogenous stimuli
1. PRRs (Pattern Recognition Receptor)
for:(1) PAMPs from pathogens(2) DAMPs (DangerAssociated Molecular Patterns) from host cells
2. Deregulated immuneresponses to these
stimulileading to• Infectious diseases• Autoimmune
disorders• Allergy • “Cancer
development”
An infection case of inflammation
Macrophages release cytokines and initiate an
inflammation response during infection
Leukocytes transmigrate to infection sites
Trafficking molecules in the multi-step adhesion cascade
An overview of leukocyte migration at sites of
inflammation
Inflammatory cytokines secreted by macrophages
(IL-8)
Resolution of acute inflammation
Lipid mediator class switching:PGE2, Leukotrienes => Lipoxins
Lipid mediators in Pro- & Anti-inflammatory responses
Role of macrophages in resolution of inflammation
Key Concepts about Inflammation-II
4. Dysregulation of any step in the inflammation process leads to diseases.
5. While acute inflammation is a part of the defense response, chronic inflammation leads to inflammatory disorders, diabetes, atherosclerosis, & “Cancer.”
6. Malignant cells actively turn the inflammation process to become the chronic status.
7. Chronic inflammation creates a microenvironment for cancer progression.
Outline
1. Roles of the immune system in cancer development
2. Overview of Inflammation
3. Inflammation, The NF-kB pathway, and Cancer Development
4. Tumor microenvironment and Tumor-Associated Macrophages
Question Question
Q: Whether all the inflammation is the same?
Role of chronic inflammation in promoting cancer development
Pathways connecting inflammation & cancers
Oncogenes & Cancer-related Inflammation
Hallmarks of Cancer-2000
Inflammation
Inflammation
Inflammation
Inflammation is the 7th hallmark of cancer
Mantovani, A., Nature, 20091
Hallmarks of Cancer-2011
Hanahan, D. & Weunberg, RA, Cell , 2011
Inflammatory network in cancer
The NF-kB pathway is the key underlying pathway promoting
cancer
The NF-kB Pathway
1. Inflammation
2. Innate immune responses
3. Survival
NF-kB induces cytokines to promote tumor survival
Association of inflammation with cancers
Outline
1. Roles of the immune system in cancer development
2. Overview of Inflammation
3. Inflammation, The NF-kB pathway, and Cancer Development
4. Tumor microenvironment and Tumor-Associated Macrophages
R. A. Weinberg, Cell 2011
The Cells of the Tumor Microenvironment
Signaling Network in the Tumor Microenvironment
A model of innate & adaptive immune cells in cancer
development
Cancer cell necrosis promotes tumor progression by recruiting macrophages
Macrophage polarization during tumor progression
Tumor-associated macrophages in promoting
cancer
Tumor-associated macrophages in promoting
cancer
Hanahan, D. & Weunberg, RA, Cell , 2011
Targeting of Hallmarks of Cancer
The End & Thank The End & Thank YouYou
Figure 1
Source: Cell , Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013)
Copyright © 2011 Elsevier Inc. Terms and Conditions
Lipid mediators in Pro- & Anti-inflammatory responses
