Download Proliferation

Cancer associated fibroblasts and tumor cells: a diabolic cross-talk
driving cancer progression
Prof. Dr. rer.nat. Gerhard Unteregger
Clinic of Urology
Saarland University
Medical Center
Homburg/Saar - Germany
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Tumor: A never healing wound ?!
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Crosstalk: Not restricted to malignant tissue!
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Crosstalk: Not restricted to malignant tissue!
•
•
•
Bell et al., J. Invest. Dermatol. 1983: „The reconstitution of living skin.“
Keratinocytes
Mackenzie & Fusenig, J. Invest. Dermatol.,1983:
“Regeneration of organized epithelial structure.”
Asselineau & Prunieras, Brit. J. Dermatol., 1984:
“Reconstruction of simplified skin: control of fabrication.”
Air-exposed
+/- Ca2+
Collagen I
Medium
Collagen I gel with fibroblasts
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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The complex composition within the prostate tissue
...but the microevironment appears to be a little bit more complex!






epithelial cells
basal cells
luminal cells
transit amplifying cells
stem cells
neuroendocrine cells
stroma cells
 fibroblats
 myofibroblasts
 endothelial (progenitor) cells
 macrophages
Extracellular Matrix
 epithelial – mesenchymal transitions
 mesenchymal – epithelial transitions
 mesenchymal – mesenchymal transitions
There is a strong communication within this network:
= Co-evolution?
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Fibroblasts as Co-factors in Prostate Development and Cancer
Fibroblasts are critical determinants
in prostatic cancer growth and
Dissemination.
Chung LW
Cancer Metastasis Rev. 1991
Oct; 10(3): 263-74
Stroma and Epithelial cells determine by paracrine interaction
normal and malignant development!
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Epithelial cells and Fibroblasts in Prostate
Stroma
Normal Prostate Gland
Basal Cells
Invasive Prostate Cancer
Especially Basal Cells are in close contact to the stroma compartment
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Receptors enables a permanent dynamic non-diabolic cross-talk
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Cancer associated fibroblasts and tumor cells: a diabolic cross-talk
driving cancer progression
We focus on Cancer Associated Fibroblasts (CAF) :
Are they a specific cell type or only a phenotype?
• Where do they come from?
• Charcterization by phenotype?
• Characterization by function?
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Origins of CAF – some ideas
P. Cirri & P. Chiarugi: AmCancRes 2011; 1(4);482-497
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Origins of CAF – some more ideas
Otranto et al. Cell Adesion & Migration 2012: 6:3; 203-219
Changes in the ECM stiffness
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Feed-back-loop enables a co-evolution of CAF and Cancer cells
P. Cirri & P. Chiarugi: AmCancRes 2011; 1(4);482-497
ECM-remodelling: Stiffness of ECM
= Mechanical stress!
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Niche-to-niche migration of BM and tumor cells.
The transit of BM and tumor cells from their respective
niches is a multidirectional pathway. Hematopoietic
cells are mobilized from the BM niche in response
to tumor-secreted chemokines and subsequently
home to both the primary tumor microenvironment
and peripheral niches. BMDCs homing to
the primary tumor niche may remain in an undifferentiated
state in the form of HPCs, EPCs, MSCs, or GR-1+
CD11b+ MDSCs; or may differentiate into more specialized
cell types including TAMs. Early BMDCs in
transit to premetastatic peripheral niches likely possess
an undifferentiated status as HPCs or myeloid-precursor
cells, and at later stages involve homing of EPCs.
Metastasizing tumor cells subsequently travel to peripheral
niches occupied by BMDCs.
Wels et al. Migratory neighbors and distant invaders:
tumor-associated niche cells. GENES DEVELOP. 2008
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Fibroblasts as Co-factors in Prostate Development and Cancer
Microenvironment as a pivotal co-factor was described a lot of years ago…
Reconstituted basement membrane promotes morphological and functional differentiation of primary human
prostatic epithelial cells. Fong CJ et al. Prostate 1991; 19(3):221-35
Acceleration of Human Prostate Cancer Growth in Vivo by Factors Produced by Prostate and Bone Fibroblasts.
Gleave M et al. Cancer Research 1991; 51: 3733-3761
Growth of an androgen-sensitive human prostate cancer cell line, LNCaP, in nude mice.
Lim et al. Prostate 1993; 22(2): 109-118
Regulation of prostate-specific antigen gene expression in LNCaP human prostatic carcinoma cells by growth,
dihydrotestosterone, and extracellular matrix. Guo Y et al. Prostate 1994; 24(1):1-10
Prostate epithelial differentiation is dictated by its surrounding stroma.
Chung LW and Davies R. Mol Biol Rep. 1996; 23(1):13-19
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Cancer associated fibroblasts and tumor cells: a diabolic cross-talk
driving cancer progression
Cancer Associated Fibroblasts (CAF) :
Where do they come from?
•
•
•
•
•
Resident within the tumor/organ
Phenotypic switch into Myofibroblasts
EMT and MMT contribute to phenotypical changes
Circulating cells of different origin will contribute,too
Disclosure of the nature and origin remains a challenge
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Cancer associated fibroblasts and tumor cells: a diabolic cross-talk
driving cancer progression
We focus on Cancer Associated Fibroblasts (CAF) :
Are they a specific cell type or only a phenotype?
• Where do they come from?
• Charcterization by phenotype
• Characterization by function?
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
„Phenotypic Characterization of CAF´S“
D Wever O. et al. Int. J. Cancer 2008;129: 2229-2231
A Challenge!
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Fibroblasts as Co-factors in Prostate Development and Cancer
Strategies to disclose phenotype and function!
“Cancer –associated-Fibroblasts CAF”: Are they really defined? How they are defined?
How they are prepared? Distance beetwen tumor-epithelial cells: 50-100-200-500μm ?
• By isolation of “fibroblasts ” from TUR (normal) and Prostatectomy (CAF) using digestion
(SH Lang, M. Stower and NJ Maitland, Br.J. Cancer (2000) 82(4), 990-997
• Immortalization of NAF and CAF by hTERT
N. Paland et al. Mol Canc Res (2009) 7(8), 1212-1223
• Embryonic rat urogenital sinus mesenchyme (UGM)
K. Ishii et al. Endocrine-Related Cancer (2009) 16, 415-428
• NAF and CAF from BPH and Prostatectomy using digestion – activated by TGF-ß
E. Giannoni et al. CancRes (2010) 70(17), 6945-6956
• Isolation of CAF and NAF and outgrowth as explants using selective media and coatings
D.Peehl and R. Sellers Prostate (2000) 45, 115-123
• Isolation from explants and characterization by IC (Vimentin, SMC, CD90)
J.A. Tuxhorn ClinCancRes (2002) 8, 2912 -2923
• Isolation from histological examined regions*, digestion, centrifugation, MACS and FACS analysis!
L.E. Pascal et al. BMC Cancer (2009) 9, 317 * parallel sections were examined additionally!
Conclusions: Most NAF/CAF were not comprehensively characterized
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Strategies to disclose the role of “Cancer associated fibroblasts”
in tumor development and progression:
Fibroblasts as Modulators in Primary Cell Cultures of Prostatic Carcinoma
Selection toward diploid cells in prostatic carcinoma derived cell cultures.
Ketter R. et al. Prostate 1996; 28(6): 365-71.
A new serial transfer explant cell culture system for human prostatic cancer tissues
preventing selection toward diploid cells.
Zwergel Th. et al. Cancer Genet. Cytogenet. 1998; 101 (1): 16-22
Origin of our „CAF“ used in these experiments:
Selection of outgrowing cells from patients specimens after Prostatectomy:
Examination by an experienced Pathologist and by parallel histological analysis –
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Strategies to disclose the role of “Cancer associated fibroblasts”
in tumor development and progression
The most important question considering the experimental design:
Different strategies for NAF/CAF preparation
Isolation of stroma by LCM
Isolation of living cells*
Only descriptive
Alignment to Histology
Contamination
Heterogeneous
Selection
Functional analysis
Changes in gene expression
Genetic modification
Really „CAF?“
But: Really „CAF?“
* Stability of phenotype and function in vitro?
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Strategies to disclose the role of “Cancer associated fibroblasts”
in tumor development and progression
Recovery of epithelial cells and fibroblasts w/o digestion
by selective outgrowth using coating and specific media
Primary cell culture
forming a monolayer
Epithelial cells
Primary cell culture
forming a monolayer
CAF/ NAF fibroblasts
Particle
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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„Phenotypic Characterization of CAF´S“
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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miRNA-pattern as markers for CAF?
Microarray analysis; comparison
of microRNA expressionpatterns
of fibroblasts from invasive tumour,
normal urothelial tissue fibroblasts
and foreskin fibroblasts as control.
Red high regulation; green low
Regulation.*
*Specific protein and miRNA patterns characterise
tumour-associated fibroblasts in bladder cancer
Astrid Enkelmann … Kerstin Junker
J Cancer Res Clin Oncol (2011) 137:751–759
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
The long way from normal prostate development to CRPC
Changes in the behavior, function and localisation of Prostate Epithelial (Cancer) Cells
are under control of T/DHT and AR (and several other factors) and triggered by the
environment.
Differentiation
Proliferation
Invasion
Survival*
Extravasation
(vessel)
Organrestricted
PrCa
Association w.
Macrophages
Embolies
2nd Tumor+
(bone)
Attachment
Proliferation
Stem cells?
AR+
Invasion
MMP`s
MET
*as circulating tumor cells
+ Metastasis
Detachment
Migration
MMP`s
EMT
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Co-cultivation systems (6-24 well systems)
Cells are cultivated in the membrane insert (top) and/or bottom of a corresponding plate
Sekretom
cell type 1
membrane
cell type 1
cell type 2
cell type 2
Sekretom
Important: Not easy to discriminate the origin of secretom!
 Functional analysis is more convenient
 Standard assays (e.g. WST) can be adapted
 Microscopic examination difficult
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Verification of CAF-mediated functions
Co-culture as one tool to
proof CAF-TC crosstalk
Lang&Maitland
Lang
+/- conditioned
Medium
LNCaP
Stroma
PC-3
bPS+/tPS
CI-Gel
Stroma enhances
Proliferation of
Tumor cells (XTT)
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
*Norman Maitland
attending our annual
AuF Meeting - Berlin
2012
Changes from “normal” to “activated” fibroblasts
by
Genom
Function
Influence on
Production of
Proliferation
Migration
Invasion
EMT
AR-Activation
Stemness
Cytokines
SDF
Growth factors
= Secretome
Genotyping - Epigenetic –
Phenotype
CGH
Methylation
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
SMA
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Crosstalk within a tumor region
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Changes from “normal” to “activated” fibroblasts
Lang&Maitland (2000)
Function
PETMembrane
0.4µm
+/- conditioned
Medium
LNCaP
Stroma (fibroblasts)
influence of normal and cancer-associated fibroblasts on the
Influence on Differential
growth of human epithelial cells in an in vitro cocultivation model of prostate cancer.
Proliferation
Paland N, et al. Mol Cancer Res. 2009 7(8)
Migration
Invasion
EMT
AR-Activation
Bhowmick NA, Hayward SW. Cancer Res. 2011 71(4):
Altered TGF-β signaling in a subpopulation of human stromal cells promotes prostatic
carcinogenesis. Franco OE, Jiang M, Strand DW, Peacock J, Fernandez S, Jackson RS 2nd, Revelo MP,
The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic
Epithelial Cell Proliferation trough Paracrine Mechanisms. : Bavikl et al. Cancer Res. 2006 66(2)
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Changes from “normal” to “activated” fibroblasts
Tumor samples (Prostatectomy)
PET-Insert
Medium
Membrane 8 µm
Function
Matrigel
Tumor Spheroids
Compan.plate
Matrigel
Collagen I
Collagen I
Fibroblasts (CAF)
Replaced by SDF1
Influence on
Proliferation
Migration
Invasion
CAFas attractant
EMT
AR-Activation
Same using SDF1
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* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
Mechanisms of invasion: Movement and enyzm activities
Function
Prostate Stromal Cell-Derived Hepatocyte Growth Factor Induces invasion of
Prostate Cancer Cell Line DU-145 through Tumor-Stromal Interaction.
K. Nishimura et al. Prostate 1999; 41.
Stromal-epithelial interactions influence prostate cancer cell invasion by altering the
Balance of metallopeptidase expression.
LA Dawson et al. Br J Cancer 2004; 90.
Influence on
Proliferationn
Migration
Invasion
EMT
AR-Activation
Regulation of migration of primary prostate epithelial cells by secreted factors from
prostate stromal cells. X. You et al. Experimental Cell Res. 2003; 288.
Stromal myofibroblasts are drivers of invasive cancer growth.
O. De Wever et al. Int J Cancer 2008; 123.
Estrogens Promote Invasion of Prostate Cancer Cells in a Paracrine Manner through
Up-Regulation of Matrix Metalloproteinase 2 in Prostatic Stromal Cells.
L.Yu et al. Endocrinology 2011; 152.
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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EMT = Epithelial-Mesenchymal-Transition
Temporary shift in differentiation allowing enhanced mobility
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Crosstalk's between Tumor cells and Microenvironment
Considering the “Secretome”
+ECM!
O.E. Franco et al. (2010): Cancer associated fibroblasts in cancer pathogenesis. SemCell&DevelopBiol
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Fibroblast derived Factors inducing EMT*
 TGF-ß
 oxidative stress
 HIF-1α
 ROS
 Wnt//ß-Cat
 KGF
 HGF
* Acquisition of metastatic and aggressive phenotypes:
 Mesenchymal morphology
 Resistance to drugs , stress and anoikis
 Enhanced migratory and invasive properties
 Inhibition of senescence
 Immunosuppression
Metastasis Update: Human Prostate Carcinoma Invasion via Tubulogenesis.
Nagle RB, Cress AE.
Prostate Cancer. 2011;2011:249290. Epub 2011 Jun 21.
Department of Pathology, The Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA.
Abstract
This paper proposes that human prostate carcinoma primarily invades as a cohesive cell collective through a
mechanism similar to embryonic tubulogenesis, instead of the popular epithelial-mesenchymal transformation
(EMT) model. Evidence supporting a tubulogenesis model is presented, along with suggestions for additional
research. Additionally, observations documenting cell adhesion molecule changes in tissue and stromal
components are reviewed, allowing for comparisons between the current branching morphogenesis models and
the tubulogenesis model. Finally, the implications of this model on prevailing views of therapeutic and
diagnostic strategies for aggressive prostatic disease are considered.
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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What is the best technology to characterize the environment completely?
Proteomic analysis of primary colon cancer-associated fibroblasts
using the SELDI-ProteinChip platform.
Z. Wang et al. Biomedicine & Biotechnology. 2012 13(3).
FAP only weak expressed
SMA overexpressed in 4/6 samples
3 “new” proteins: FMRFamide related peptides, ILG-II, Thyß-4-like protein
Identification of stromally expressed molecules in the prostate by tag-profiling of
cancer-associated fibroblasts, normal fibroblasts and fetal prostate.
B Orr1 et al. Oncogene (2012) 31,
671 transcripts enriched in CAF`s (organogenesis)
356 transcripts decreased as compared to NAF´s (cell cycle associated)
Restriction to secreted/membrane bound proteins:
ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6,
SPARC, STC1 and ZEB1
Specific and variable expression only in prostate cancer and fetal prostate fibroblasts
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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mRNA Array analysis* of matches pairs of NAF/CAF
MAP3K1
SCARB1
S10010
*Cooperation with M. Caraglia/G. Vitale
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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mRNA Array analysis* of matches pairs of NAF/CAF
Fold change upregulated
MAP3K1
RNY3
SCARB1
PHLDB2
MAGT1
NBPF11
1,816 
1,719 
1,565 
1,510 
1,456 
1,237 
Fold change downregulated
S100A10
SNAPC2
1,589 
1.541 
MAP3K1 (MEKK1)
 Associated with focal adhesion
 Overexpression in pancreatic cancer cells
 Depletion by siRNA inhibits invasion and migration
 Tranmitting signals for ECM homeostasis and epithelial cell
migration
 Regulates detachment of migrating fibroblasts
 Less data available from prostate cancer
SCARB1(SRB1)
 Membrane bound protein receptor for HDL
 Facilitates influx of Cholesterol into the cells
 Increased expression in AR-independent cells
 Enables the synthesis of DHT from Cholesterol
 Expression involved in CRPC
S100A10
 Plasminogen receptor
 Present on the cell surface as heterotetramer
 Plasmin activates Marix-Metallo-Proteinases
 Essential for Tumor-promoting macrophages into tumor sites
 Increased expression in CRPC
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Changes in gene expression following/responsible for EMT
EMT Signature
Cancer Stem Cell Phenotype induced by CAF`s
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
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E-Cadherin-Vimentin-Notch-1-PDFG-D-NF-kB-ZEB1
Only Notch-1 overexpressed in bone metastasis
Variable expression and differences between ITF and center of the tumor
CAVE: EMT is a transient process and cells can re-differentiate by MET!



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Sox2, Nanog, Oct4, Lin 28B, Notch1 increased
miR-200 decrased
Re-expression of miR-200 inhibits prostate spheres forming
Re-expression of miR-200 reduces Notch1 and Lin28B expression
Molecular signature of epithelial-mesenchymal transitions (EMT) in human prostate cancer
bone metastasis.
S. Sethi et al. Am J Transl Res 2011, 3(1). Histological sections
Epithelial to Mesenchymal Transition is Mechanistically linked with Stem Cell Signatures in Prostate
Cancer Cells.
D. Kong et al PLoS one 2010; 5(8. PC-3 cell line
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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The long way from normal prostate development to CRPC
Changes in the behavior, function and localisation of Prostate Epithelial (Cancer)
Cells under the Control of T/DHT and AR (and several other factors)
and triggered by the environment
Differentiation Proliferation
Invasion
Survival*
Extravasation
Organrestricted
PrCa
Invasion
MMP`s
MET
2nd Tumor+
Attachment
Proliferation
Stem cells?
AR+
Association w.
Macrophages
Embolies
Detachment
Migration
*as circulating tumor cells
MMP`s
+ Metastasis
EMT
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Contribution of CAF to AR-mediated gene regulation:
 CAF express AR at low levels
 T/DHT mediated activation of these AR contributes to AR activities
 AR activation occurs by synthesis of T/DHT from DHEA
 T/DHT independent growth factor promote prostate cancer cells growth
*Prostate stromal cells and LNCaP cells coordinately activate the AR through synthesis
of testosterone and DHT from dehydroepiandrosterone DHEA.
A.Mizokami et al. Endocrine-related cancer 2009; 16.
Co-culture of CAF with LNCaP cells – Quantification of androgens by LC-ESI-MS/S
RT-PCR of 3ß-HSD and 17ß-HSD Enzymes (HSD = Hydroxysteroid-Dehydrogenase
Effects of Androgen Receptor and Androgen on Gene Expression in Prostate Stromal
Fibroblasts and Paracrine Signaling to Prostate Cancer Cells.
M.J. Tanner et al. PLoS one 2011, 6(1).
WPMY-1 transfected to express AR at levels like LNCaP
+/-DHT changes gene expression profile (like TGF-ß, Hedgehog, Wnt and MAP Kinase)
Conditioned medium from DHT/WPMY.1 increases growth of LNCaP cells
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Strategies to disclose the role of “Cancer associated fibroblasts”
in tumor development and progression
and for a comprehensive characterization!
Changes from “normal” to “activated” fibroblasts
by
Genom
Function
Influence on
Proliferation
Migration
Invasion
EMT
AR-Activation
Production of
Cytokines
SDF
Growth factors
Genotyping Epigenetic Transcription Phenotype
CGH
Methylation
Senescence
Co-Evolution
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
RNA
miRNA
SMA
FAP
PDFRß
CD90
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Molecular genetic comparison of cancer and non-cancer-associated
fibroblasts in prostate cancer*
Epigenetic modifications in Fibroblasts
Global hypomethylation of genomic DNA in cancer-associated myofibroblasts.
Jiang L, Gonda TA, Gamble MV, Salas M, Seshan V, Tu S, Twaddell WS, Hegyi P, Lazar G, Steele
I, Varro A, Wang TC, Tycko B Cancer Res. 2008 Dec 1;68(23):9900-8.
Specific age-associated DNA methylation changes in human dermal fibroblasts.
Koch CM, Suschek CV, Lin Q, Bork S, Goergens M, Joussen S, Pallua N, Ho AD, Zenke M, Wagner W; PLoS
One. 2011 Feb 8;6(2):e16679.
Comparison 23 vs 60 years old donors! Hypermethylation in the aged group!
No significant changes during subcultivation!
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Molecular genetic comparison of cancer and non-cancer-associated fibroblasts
in prostate cancer*
Conclusion and Future Trends
Secretome by Proteomics
Tumor cell
ECM
CAF/NAF







CAF/TC crosstalk highly complex and dynamic
Co-Evolution of CAF/TC
CAF characterisation difficult
Comprehensive characterisation of “Secretome”
New and better models required
Hormone metabolism in CAF unclear
Contribution of CAF to CRPC likely?
Secretome by Hormones/Metabolites
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Viability of prostate cancer cell lines after ZOL-application
* Cooperation with Prof. Dr. M. Caraglia & Dr. G. De Rosa
Comparison between flat and 3D cell cultures*
120
100
80
60
40
Free ZOL [20 µM]
PGNP_ZOL [20 µM]
NP_ ZOL [20 µM]
20
ph
er
es
ro
s
et
e
om
os
H
H
at
ph
er
es
0
Fl
Absorption in % compared to
control
PC-3
Cell culture system
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Molecular genetic comparison of cancer and non-cancer-associated
fibroblasts in prostate cancer*
Gravity contributes to the Fibroblast-Tumor Cell Interaction in-vitro!
Three-dimensional co-culture models to study prostate cancer growth, progression,
and metastasis to bone
Ruoxiang Wang, a, Jianchun Xua, Lisa Juliettec, Agapito Castillejac, John Loveb, Shian-Ying Sunga, Haiyen
E. Zhaua, Thomas J. Goodwinb, Leland W.K. Chunga
a Department of Urology, Molecular Urology and Therapeutics Program, Emory University School of
Medicine, Atlanta, GA 30322, USA
b NASA Johnson Space Center, Houston, TX 77058, USA
c Wyle Laboratories, Houston,
Columbia 1st Fev 2003 harbouring Co-Cultivation Experiments on board
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Thanks to the audience!
Thanks to all which contributes to our results:
Helga Angeli
Eva Schmidt
Volker Jung
Kerstin Junker
Michele Caraglia
Giovanni Vitale
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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Aber auch die Bewegung spielt eine Rolle!
HUVEC cultivated onto/into flow-chambers (IBIDI
24 h w/o Flow
24 h +
48 h +
159p6
161p1
* Molecular Cell- and Tumour Biology * Summer 2013 * Naples*
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