TUMOR

MICROENVIRONMENT
SITI BOEDINA KRESNO
POSTGRADUATE STUDIES BIOMEDICAL SCIENCES, FKUI
DHARMAIS NATIONAL CANCER CENTER

Tumor is not just cancer cells

Fibroblast

Cancer cells make up

only a small portion of a
tumor

Myofibroblast

Endothelial cells

Pericytes

Smooth muscle

Adipocyte

Tumors contain > 90%

stromal cells
Large amount of
extracellular matrix
(ECM) materials

What is it like in there?

Hypoxic
Acidotic
Necrotic
Disorganized
Increased interstitial pressure
Leaky blood flow
Actively dividing cells
Lympathatic system not adequate (to remove fluid)

The tumor environment is quite

complex.

Immune
Cells
Fibroblast
Normal
Stroma

EC
M

Tumor
stroma

Basement
membrane

Normal
Cells

Cancer
Cells

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

THE EXTRACELLULAR
MATRIX (ECM)

A.

Angiogenesis and
lymphangiogenesis
depend on the ECM

A.

The ECM plays

multiple roles in
tumor imflammation.

Abnormal ECM
promotes cancer
progression

Lu, Weaver & Werb; JCB 2012

THE TUMOR MICROENVIRONMENT

Koontongkaew; J Cancer 2013

IMMUNE CELLS AND INFLAMMATION

Macrophages

Produces growth factors. Proteolytic enzymes, chemokines,

pro-angiogenic factors (VEGF, IL-8 may kill tumor cells) .

Lymphocytes

Release chemokines and growth factors (important in

metastasis).

Granulocytes

Release many factors including reactive oxygen and

metabolites

Mast Cells
NK Cells

Releases many factors that alter vascular permeability and

alter immune responses

More of the same.

Inflammatory R/
contribute to the
creation of TME

Cyclooxygenase
and
Lipooxygenase

Aberrant arachidonic
(AA) pathway (COX &
LOX) is activated
during tumorigenesis
COX and LOX :
Stimulate proliferation
Inhibit apoptosis

Antiapoptosis
P53 inactive
BCL2
PPARs

Proliferation
MAPKs
PKC
AKT

Invasion /
metastasis
E-cadherin
CD44
MMP2
MMP9

Angiogenesi
s
VEGF
MMPs

Induce angiogenesis
Enhance invasion &

metastasis

TUMOR ASSOCIATED INFLAMMATION IN

TUMOR MICROENVIRONMENT
Koontongkaew.J Cancer 2013

Protumor properties of
TAM derive from
regulation of :
Angiogenic
programming
Production of soluble
mediators that support
proliferation, survival &
invasion
Direct & indirect
suppression of CTL
activity

Ruffell, Alfara, Coussens ;

Trends in Immunol 2012

DIFFERENTIAL MACROPHAGE
PROGRAMMING IN THE TUMOR
MICROENVIRONMENT

DIVERSE ROLE OF TUMOR ASSOCIATED MACROPHAGE IN TUMOR

MICROENVIRONMENT

Immune
suppression

Inflammation
Initiation

progression
Secretion of immune
suppressive factors:
IL10, TGF-b, ROS
Recruitment of Treg,
CCL22
Expression of immune
suppressive surface
mediators (B- fam
proteases)

Secretion of
proinflammatory factors
(TNF-a, IL2-b, IFN-g
Secretion of mutagenic
factors RNI, ROI
Efficient antigen
presentation
Tumor destruction &
tissue damage

TAM

Metastasis
progression

Secretion of ECM
degrading proteases:
MMPs, uPA, cathepsin
Secretion of pro-invasive
factors, EGF
Establishment of
metastatic niche
Survival signals for
disseminated cancer cells
(integrin a-4-b1)

Secretion of
angiogenic factors,
VEGF, PIGF, bFGF
Secretion of ECM
remodelling
proteases: MMPs,
uPA

Angiogenesis
progression

Schmid & Varmer; Vasc Cell 2012 (modified)

DIFFERENCE BETWEEN NORMAL TISSUE AND MALIGNANT

TME

Zhang & Liu; Pharmacol & Therap 2013

Normalized fibrotic stroma vs Tumor stroma

Tissue disorganization may drive the

epithelial-mesenchymal transition (EMT)
Functional significance

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.

DYNAMIC INTERACTION IN CANCER

Host
Tumor
microenvironment

CTC

DNA
methylation
rearrangement

Cancer
cells

RNA
miRNA

Proteins
Altered levels
Altered
processing
Other modif

Immune
response
Immune cell
profile
Auto-Ab
Cytokines

Metabolites
From cancer
cells & altered
host metab

Biomarkers can now analyze tumor microenvironment,

cancer cells & interplay between host-cancer-environment
Nat Rev Clin Oncol 2011

Stromal cells co-evolve with tumor and may

require genetic changes that facilitate growth
Exp 1

Sub-lethal irradiation of fibroblasts followed by implantation

with Pancreatic cancer cells lead to more aggressive tumors
than implantation with normal fibroblasts (Altered fib support
cancer cells better).

Exp 2

Ectopic expression of HGF or TGF-b by genetically modified

fibroblasts induces breast cancer in normal breast epithelial
cells (modified fib caused alterations in normal epithelia).

Exp 3

Alterations in p53, TGF-b receptor and others have been

seen in fibroblasts from cancer stromal tissue (carinoma
associated fibroblast, CAF).

Exp 4

Some genetic changes in stromal cells may precede the

development of cancer.

CANCER CELLS NEED STROMAL CELLS

PARADIGM

EVIDENCE

Metastatic growths have

Some experimental

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.

evidence: Breast cancer cells

placed into an immunocompromised host gave slow
growth (2 months).
Breast cancer cells mixed
with mammary fibroblasts
gave rise to tumors in 1/3
the time.

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 factor
LIF: 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

CAF derived factors

create a tumor
permissive
microenvironment
and contribute to
the metastatic
phenotype of
cancer cells

Ostman & Augsten.

Curr Opin Genet Dev
2009

INVOLVEMENT OF CAFs IN TME :

bystanders turning into keyplayers

PRIMARY AND METASTATIC TUMOR

MICROENVIRONMENT

Hanahan & Weinberg; Cell 2011

MICRO-ENVIRONMENT: Inflammation
Therapy induced
inflammation
Tumor reemergence
Resistance to therapy
Antigen presentation
Cancer cell killing

Inflammation
Caused by
environmental
& dietary
exposure

Mutation
Genomic instability
Tumor promotion
angiogenesis

Tumor
development
Tumor growth/
Survival
Genomic instability
Immunosuppression
Metastasis
Cancer cell kills

Mutation
Chronic inflammation
Genomic instability
Infection
Tumor promotion
Autoimmunity
Angiogenesis

Tumor associated
inflammation

Grivennikov et al; Cell 2010

CANCER AND ITS MICROENVIRONMENT

Interaction with the immune system
Lymphocyte response
CMI
Most
important
CD3+ CD8+
CD3+CD56+
/ NKT
TIL
Tumor
Infiltrating
Lymphocytes

CD4+CD25+
FoxP3+/Tre
g
DCs

Cytokines, growth factors and association

with Lymphocyte mobility and response
IL12, IL4, IFNg,
TNFa, IL10, TGFb

Chemokines,
CCL22, GD3,
VEGF

MICROENVIRONMENT:
Immunostimulation and immunosuppression

Finn NEJM 2008

MICROENVIRONMENT-TUMOR INTERACTION

Sato et al Cancer Microenv 2009

SEVERAL THERAPEUTIC STRATEGIES AIM AT THE TME

Zhang & Liu. Pharmacol & Therap 2013

SUMMARY
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 ??

FINAL THOUGHTS (Curiel 2007)

We need a better understanding of the
cancer microenvironment and immune
dysfunction in cancer
We need a better understanding of
targeting cancer microenvironment and
the immune effects of current agents.
Willingness of investigators to try
immune therapies will help, but they
have to be convinced.