cancer and inflamation

8/10/2019 Cancer and Inflamation

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Inflammation and Cancer

Pin Ling (), 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)


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Outline

1. Roles of the immune system in cancerdevelopment

2. Overview of Inflammation

3. Inflammation, The NF-kB pathway, and CancerDevelopment

4. Tumor microenvironment and Tumor-AssociatedMacrophages


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Cancer development & Microenvironment

1. Cancers are not only autonomous masses of mutant cells.=> Composed of other cell types?

=> fibroblasts, epithelial cells, immune cells,cellsforming blood & lymphatic vessels, & mesenchymal cells.

2. Tissue homeostasisis maintained by coordinatedinteractions 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 outcomeof hijacking microenvironmentby malignant cells

Here we focus on the relationship betweenthe immune cells and cancers.


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Paradoxical roles of the immunesystem 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


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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


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The complex relationship betweenthe immune system and cancers-I

1. Adaptive and innate immune cells regulate tissuehomeostasis 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 tocancer development.

4. In cancers, an abundance of infiltrating innate immune cells(e.g. macrophages, mast cells, and neutrophils)correlateswith increased angiogenesis and/or poor prognosis.


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The complex relationship betweenthe immune system and cancers-II

5. Long-term usage of non-steroidal anti-inflammatory drugsand selective cyclooxygenase 2 (COX2) inhibitors reducescancer incidence.

6. In cancers, an abundance of infiltrating lymphocytescorrelates with favourable prognosis.

7. Activation of anti-tumour adaptive immune responses cansuppress tumour growth

8. Polymorphisms in genes that regulate immune balanceinfluence cancer risk.

9. Genetic elimination or depletion of immune cells alters

cancer progression in experimental models.


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Outline






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Causes & Outcomes of Inflammation


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The Inflammatory Pathway


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Inflammation in innate and adaptiveimmunity

Inflammatory cells, cytokines, & chemokines

are major effectors in this process.


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PRRs for sensing infectious &endogenous stimuli

1. PRRs (PatternRecognition 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


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An infection case of inflammation


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Macrophages release cytokines andinitiate an inflammation response

during infection


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Leukocytes transmigrate to infectionsites


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Trafficking molecules in the multi-stepadhesion cascade


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An overview of leukocyte migration atsites of inflammation


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Inflammatory cytokines secretedby macrophages

(IL-8)


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Resolution of acute inflammation

Lipid mediator class switching:

PGE2, Leukotrienes => Lipoxins


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Lipid mediators in Pro- & Anti-inflammatory responses


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Role of macrophages in resolutionof inflammation


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Key Concepts about Inflammation-I

1. Inflammation- A physiological process whereby tissuesrespond to infectious & non-infectious insults(alsocalled sterile inflammation, including toxic, traumatic, orautoimmune 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


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Key Concepts about Inflammation-II

4. Dysregulation of any step in the inflammationprocess leads to diseases.

5. While acute inflammation is a part of the defense

response, chronic inflammation leads toinflammatory disorders, diabetes, atherosclerosis,& Cancer.

6. Malignant cells actively turn the inflammationprocess to become the chronic status.

7. Chronic inflammation creates a microenvironmentfor cancer progression.


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Outline






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Question

Q: Whether all the inflammation is

the same?


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Role of chronic inflammation inpromoting cancer development


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Pathways connecting inflammation &cancers


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Oncogenes & Cancer-relatedInflammation


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Hallmarks of Cancer-2000

Inflammation

Inflammation

Inflammation


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Inflammation is the 7thhallmark of cancer

Mantovani, A., Nature, 20091


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Hallmarks of Cancer-2011

Hanahan, D. & Weunberg, RA, Cell , 2011


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Inflammatory network in cancer

The NF-kB pathway is the key underlyingpathway promoting cancer


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The NF-kB

Pathway

1. Inflammation

2. Innate immuneresponses

3. Survival

F k d k


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NF-kB induces cytokines to promotetumor survival


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Association of inflammation with cancers


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Outline






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Signaling Network in the TumorMicroenvironment

A d l f i t & d ti i


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A model of innate & adaptive immunecells in cancer development


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Cancer cell

necrosispromotes tumorprogression byrecruitingmacrophages

M h l i ti d i t


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Macrophage polarization during tumorprogression


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d h


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Tumor-associated macrophages inpromoting cancer


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Hanahan, D. & Weunberg, RA, Cell , 2011

Targeting of Hallmarks of Cancer


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The End & Thank You

Figure 1


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Source: Cell , Volume 144, Issue 5, Pages 646-674(DOI:10.1016/j.cell.2011.02.013)

Copyright 2011 Elsevier Inc. Terms and Conditions

Li id di t i P & A ti
http://www.cell.com/abstract/S0092-8674(11)00127-9http://www.cell.com/cellpress/TermsandConditionshttp://www.cell.com/cellpress/TermsandConditionshttp://www.cell.com/abstract/S0092-8674(11)00127-9http://www.cell.com/abstract/S0092-8674(11)00127-9http://www.cell.com/abstract/S0092-8674(11)00127-9


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Lipid mediators in Pro- & Anti-inflammatory responses


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cancer and inflamation

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