Transcript Cancer development

Inflammation and Cancer
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 & Microenvironment
1.
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.Here
“Tissue
is maintained
by coordinated
we homeostasis”
focus on the
relationship
between
interactions
these
diverse cell types.
the
immune between
cells and
cancers.
=> 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
Paradoxical roles of the immune
system in cancer development
1.
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
Most cancers outplay the immune system
CD45 Stain
(all immune cells)
=> Escape from cytotoxic T cell attacks
=> Make other immune cells help their survival
The complex relationship between
the immune system and cancers-I
1. 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-II
5. 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 Inflammation
The Inflammatory Pathway
Inflammation in innate and adaptive
immunity
Inflammatory cells, cytokines, & chemokines
are major effectors in this process.
PRRs for sensing infectious &
endogenous stimuli
1. PRRs (Pattern
Recognition Receptor) for:
(1) PAMPs from pathogens
(2) DAMPs (Danger
Associated Molecular
Patterns) from host cells
2. Deregulated immune
responses to these stimuli
leading 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- & Antiinflammatory 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
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
The Cells of the Tumor Microenvironment
R. A. Weinberg, Cell 2011
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
Targeting of Hallmarks of Cancer
Hanahan, D. & Weunberg, RA, Cell , 2011
The End & Thank You
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- & Antiinflammatory responses