tme-rskd 240615.pdf

7/23/2019 TME-RSKD 240615.pdf

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S I T I B O E D I N A K R E S N O

P O S T G R A D U A T E S T U D I E S B I O M E D I C A L S C I E N C E S , F K U I

D H A R M A I S N A T I O N A L C A N C E R C E N T E R

TUMOR

MICROENVIRONMENT

Tumor is not just cancer cells

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Cancer cells make uponly a small portion of atumor

Tumors contain > 90%stromal cells

Large amount ofextracellular matrix(ECM) materials

Fibroblast Myofibroblast

Endothelial cells Pericytes

Smooth muscle Adipocyte

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What is it like in there?

Hypoxic

Acidotic

NecroticDisorganized

Increased interstitial pressure•

Leaky blood flow•Actively dividing cells

•Lympathatic system not adequate (to remove fluid)

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The tumor environment is quite complex…….

The cells in a tumor talk to each other all the time……….

Normal

Stroma

Normal

Cells

Basement

membrane

ECM

ImmuneCells

Fibroblast

Tumor

stroma

Cancer

Cells

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THE EXTRACELLULARMATRIX (ECM)

A. Angiogenesis andlymphangiogenesisdepend on the ECM

A. The ECM playsmultiple roles intumor imflamma-tion.

Abnormal ECMpromotes cancerprogression

Lu, Weaver & Werb; JCB 2012

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THE TUMOR MICROENVIRONMENT

Koontongkaew; J Cancer 2013

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IMMUNE CELLS AND INFLAMMATION

• Produces growth factors. Proteolytic enzymes, chemokines,pro-angiogenic factors (VEGF, IL-8 may kill tumor cells) .Macrophages

• Release chemokines and growth factors (important inmetastasis).Lymphocytes

• Release many factors including reactive oxygen andmetabolitesGranulocytes

• Releases many factors that alter vascular permeability andalter immune responsesMast Cells

• More of the same.NK Cells

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TUMOR ASSOCIATED INFLAMMATION INTUMOR MICROENVIRONMENT

Inflammatory R/contribute to thecreation of TME

Aberrant arachidonic(AA) pathway (COX &

LOX) is activatedduring tumorigenesis

COX and LOX :

Stimulate proliferation

Inhibit apoptosisInduce angiogenesis

Enhance invasion &metastasis

ProliferationMAPKs

PKC

AKT

Anti-apoptosis

P53 inactive

BCL2PPARs

Invasion /metastasis

E-cadherinCD44

MMP2MMP9

Angiogenesis

VEGF

MMPs

Cyclooxygenaseand

Lipooxygenase

Koontongkaew.J Cancer 2013

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DIFFERENTIAL MACROPHAGEPROGRAMMING IN THE TUMOR

MICROENVIRONMENT

Protumor properties ofTAM derive fromregulation of :

Angiogenicprogramming

Production of solublemediators that supportproliferation, survival &invasion

Direct & indirectsuppression of CTL

activity

Ruffell, Alfara, Coussens ;Trends in Immunol 2012

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DIVERSE ROLE OF TUMOR ASSOCIATED MACROPHAGE IN TUMORMICROENVIRONMENT

Schmid & Varmer; Vasc Cell 2012 (modified)

• Angiogenesis• progression

• Metastasis• progression

• Immunesuppression• progression

• Inflammation• Initiation

Secretion ofproinflammatory factors(TNF-a, IL2-b, IFN-g

Secretion of mutagenicfactors RNI, ROI

Efficient antigenpresentation

Tumor destruction &tissue damage

Secretion of immunesuppressive factors:

IL10, TGF-b, ROS

Recruitment of Treg,CCL22

Expression of immunesuppressive surface

mediators (B- famproteases)

Secretion ofangiogenic factors,

VEGF, PIGF, bFGF

Secretion of ECM

remodellingproteases:MMP’s,

uPA

Secretion of ECMdegrading proteases:MMP’s, uPA, cathepsin

Secretion of pro-invasivefactors, EGF

Establishment of

metastatic nicheSurvival signals fordisseminated cancer cells(integrin a-4-b1)

TAM

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DIFFERENCE BETWEEN NORMAL TISSUE AND MALIGNANTTME

Zhang & Liu; Pharmacol & Therap 2013

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Normalized fibrotic stroma vs Tumor stroma

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Tissue disorganization may drive the

epithelial-mesenchymal transition (EMT)

Activation of Matrix-Metalloproteinases (MMP-3) leads to degradation of ECM and altered gene

expression.

Genes expressed may induce EMT as well as he production of oxygen radicals that lead to

genomic DNA damage.

Functional significance

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DYNAMIC INTERACTION IN CANCER

Host

Tumormicroenvi-

ronment

Cancer

cells

CTC

DNAmethylation

rearrangement

RNA

miRNA

Proteins Altered levels

Alteredprocessing

Other modif

Immuneresponse

Immune cell

profile Auto-AbCytokines

MetabolitesFrom cancer

cells & alteredhost metab

Nat Rev Clin Oncol 2011

Biomarkers can now analyze tumor microenvironment,cancer cells & interplay between host-cancer-environment

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Stromal cells co-evolve with tumor and may

require genetic changes that facilitate growth

• Sub-lethal irradiation of fibroblasts followed by implantationwith Pancreatic cancer cells lead to more aggressive tumorsthan implantation with normal fibroblasts (Altered fib supportcancer cells better).

Exp 1

• Ectopic expression of HGF or TGF-b by genetically modified

fibroblasts induces breast cancer in normal breast epithelialcells (modified fib caused alterations in normal epithelia).Exp 2

• Alterations in p53, TGF-b receptor and others have beenseen in fibroblasts from cancer stromal tissue (carinomaassociated fibroblast, CAF).

Exp 3

• Some genetic changes in stromal cells may precede thedevelopment of cancer.Exp 4

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PARADIGM EVIDENCE

Metastatic growths have

stromal compartments

Most cancer cells will not

form cell lines; Need stromal

interactions.

Hallmarks of cancer lead to

reduced dependence on

other cells, but not total

release.

Some experimental

evidence: Breast cancer cells

placed into an immunocom-

promised host gave slow

growth (2 months).

Breast cancer cells mixed

with mammary fibroblasts

gave rise to tumors in 1/3

the time.

CANCER CELLS NEED STROMAL CELLS

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Tumors altered versions of normal tissues?!Tumor cells Hijack normal processes but in a hyper way

EGF: Epidermal growth factor

FGF: Fibroblast growth factor

HGF: hepatocyte growth factor

IGF: Insulin-like growth factor

IL: Interlukin

KGF: keratinocyte growth factorLIF: Leukemia inhbitory factor

MMP: matrix metalloproteinases

MSP: macrophage stimulatory factor

NGF: nerve growth factor

Oncostatin: a cytokine in the IL-6 family

SDF/CXCL 12: a chemokine

TGF: transforming growth factor

Wnt: wingless Int

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INVOLVEMENT OF CAF

s IN TME : bystanders turning into keyplayers

CAF derived factorscreate a tumorpermissivemicroenvironmentand contribute tothe metastaticphenotype ofcancer cells

Ostman & Augsten.

Curr Opin Genet Dev

2009

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PRIMARY AND METASTATIC TUMORMICROENVIRONMENT

Hanahan & Weinberg; Cell 2011

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MICRO-ENVIRONMENT: Inflammation

Therapy inducedinflammation

Tumor reemergenceResistance to therapy Antigen presentation

Cancer cell killing

Tumordevelopment

InflammationCaused by

environmental& dietaryexposure

MutationGenomic instability Tumor promotion

angiogenesis

MutationGenomic instability Tumor promotion

Angiogenesis

Chronic inflammationInfection

Autoimmunity

Tumor growth/Survival

Genomic instability Immunosuppression

MetastasisCancer cell kills

Tumor associatedinflammation

Grivennikov et al; Cell 2010

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Interaction with the immune system

CMI

Mostimportant

TIL

TumorInfiltrating

Lymphocytes

Lymphocyte response

CD3+ CD8+

CD3+CD56+

/ NKT

CD4+CD25+

FoxP3+/Treg

DC’s

Cytokines, growth factors and association with Lymphocyte mobility and response

IL12, IL4, IFNg,TNFa, IL10, TGFb

Chemokines,CCL22, GD3,

VEGF

CANCER AND ITS MICROENVIRONMENT

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MICROENVIRONMENT:Immunostimulation and immunosuppression

Finn NEJM 2008

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MICROENVIRONMENT-TUMOR INTERACTION

Sato et al Cancer Microenv 2009

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SEVERAL THERAPEUTIC STRATEGIES AIM AT THE TME

Zhang & Liu. Pharmacol & Therap 2013

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Microenvironment of cancer (TME)• Stromal cells necessary for cancer• Cross-talk between tumor cells and TME• Significant involvement of cytokines & chemokines• Inflammatory reactions contribute to environment favors cancer

development

Immune-stimulation vs immune-suppression

At time of diagnosis: suppression > surveillance

Main factors involved in suppression

• Cellular: Treg, pDCs, MDSC, TAM (B7-H4)

• Soluble: TGF-b, GD3, CCL22, MIF, VEGF

Prospects for therapeutic intervention

• Promising targets in TME•More basic research• TME-based treatment ??

SUMMARY

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FINAL THOUGHTS (Curiel 2007)

We need a better understanding of thecancer microenvironment and immunedysfunction in cancer

We need a better understanding oftargeting cancer microenvironment andthe immune effects of current agents.

Willingness of investigators to tryimmune therapies will help, but theyhave to be convinced.

tme-rskd 240615.pdf

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