inflammation and cancer pin ling ( 凌 斌 ), ph.d. ext 5632; lingpin@mail.ncku.edu.tw references:...

Inflammation and Inflammation and CancerCancer

Pin Ling ( 凌 斌 ), 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 & 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