Inflammation and Cancer

Pin Ling ( ), Ph.D.

ext 5632; lingpin@mail.ncku.edu.tw
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

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-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

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