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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.