Download Cell Structure Tumor Microenvironment

Cell Structure
&
Tumor Microenvironment
Semra Aygun-Sunar, PhD
Department of Cell Stress Biology
[email protected]
RPN-530 Oncology for Scientist-I
October 3, 2013
Reading
Book
• “The Biology of Cancer”, Chapter 13 Robert Weinberg,
Garland Science, 2006
• “Molecular Biology of the Cell” (Fifth Edition). Bruce Alberts,
Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts,
Peter Walter; 2008
Review
• Hanahan & Weinberg, Hallmarks of Cancer: the next
generation. Cell. 2011. 144: 646-674
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Overview of this lecture
• Cells & cell theory
• Studying of cells using microscopes
• Structure and function of specific components include
mitochondria, golgi, endoplasmic reticulum, cytoskeleton,
extracellular matrix…..
• Cancer cells
• Tumor microenvironment:
!
“Hypoxia” and “stromal cells”
• Communication of cells with the tumor microenvironment
!
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Cell
“is the functional and smallest unit in every organism ”
• The cell was first discovered by
Robert Hooke (in 1665).
• The cell theory was developed by
Matthias J. Schleiden, Theodor
Schwann and Rudolph Virchow
(Ref: The Molecular Probes®
Handbook-11th Edition, 2010, Invitrogen)
Main principles of the cell theory
• All living organisms are composed of cell(s).
• Cells are the essential unit of structure and function in
organisms
• Cells are produced through the division of pre-existing cells
(mitosis)
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Studying Cells
Light microscopy
• uses visible light (ranges from 0.4 µm (for violet) to 0.7 µm (for deep red) that
transmitted through or reflected from specimen
• can view living cell to see their compartments
• gives 1,000X magnification
Ø Types of light microscopes
1. Bright field
microscopy
Passes light
directly through
specimen
2. Dark-field
microscopy
Light scattered
by specimen
3. Phase-contrast
microscopy
Alter light waves
to enhance the view
of specimen
4. Differential interference
contrast microscopy
(DIC or Nomarski)
Give specimens a 3D
appearance
The same fibroblast cell in culture shown using different types of light microcopies.
Ref: “Molecular Biology of The Cell”, 5th edition. Alberts et al., 2008. Chapter 9, p.584
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Studying Cells
Electron microscopy
• uses beam of highly energetic electron to illuminate the specimen
• has high magnification and high resolution
TEM vs SEM
cells must be dead and specimen require
specifically preparations: can be cut/sectioned or
T
coated in gold metal
Ø Types of electron microscopes
!
Transmission Electron Microscopy (TEM)
• uses the electrons that pass through specimen
• is used for analyzing sections
• shows only structure of cell
• gives a 2D views
• gives 1,000-500,000X magnification
!
Scanning Electron Microscopy (SEM)
• uses the electrons reflected from a specimen
• is used for analyzing surface of the specimen
• shows defined organelles inside cell
• gives a 3D views
• gives 10-300,000X magnification
Cell Structure & Tumor Microenvironment
E
M
S
E
M
Cilia lining the trachea
under TEM and SEM
http://www.med.nus.edu.sg/ant/
histonet/tacsem/tac20.sem.gif
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Studying Cells
Fluorescent molecules
• absorb light at one wavelength called as Excitation, and emit it
at another long wavelength called as Emission
Chlorophyll has endogenous auto-fluorescence
Fluorescent protein (GFP), Fluorescent probes are used to study
the organization and function of living organism.
Fluorescence probes
Protein probe
Ex
(nm)
Em
(nm)
Em
color
FITC
488
525
Green
Nucleic acid probe
Ex (nm)
Em
(nm)
Em color
DAPI
350
470
Blue
Hoechst 33342
343
483
Blue
Stably transfected human cervix carcinoma
HeLa cells expressing GFP
http://www.evrogen.com/products/
TurboGFP/
TurboGFP_Detailed_description.shtml
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Studying Cells
Fluorescence microscopy
• exposes specimen to ultraviolet, violet, or blue light
• excites and detects Fluorescent materials
Epithelial cells stained with
DAPI (blue) and two antibodies
(green and red) via
immunofluorescence
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Studying Cells
Confocal microscopy
• is used with Fluorescent specimens
• has two parts: optical sectioning
and 3D-reconstraction
-- takes a series of images to record
-- computer generate a movie showing
the 3D rotation of the image
Confocal fluorescence microscopy of focal
adhesion and actin cytoskeleton in COS-7 cells
revealed with triple labeling using TRITCconjugated phalloidin, anti-Vinculin and DAPI.
http://www.millipore.com/antibodies/flx4/
cell_structure&tab1=5&tab2=3#tab2=3:tab1=5
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Studying Cells
Wide-field epifluoresence vs Confocal microscopy
microscopy
• gives nice images that have in-focus
• gives very nice images that
light
have both in-focus and out-focus • does performs optical sectioning of
light
thick samples,
•works with very thin specimens • is ability to control depth of field,
or when a thick specimen is cut
• provides 3D-image reconstruction,
into sections.
• detects very weak fluorescent
signals,
• generates high-resolution images,
• has more color possibilities.
http://www.itg.uiuc.edu/
technology/atlas/
microscopy/confocal.htm
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Types of Cells
1. Prokaryotic cells: Archae and bacteria
(no nucleus, no membrane-bound organelle, contain primitive
cytoskeleton and circular-shaped DNA)
2. Eukaryotic cells: Protists, fungi, plants, animal (including human)
(contain various membrane-bound organelles, cytoskeleton,
chromatin and chromosome)
Prokaryotic cell
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vs
Eukaryotic cell
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Plasma membrane (or cell membrane)
Ø Structure
• Fluid Mosaic Model
• Phospholipid bilayer (Hydrophilic polar heads face outside and
hydrofobic nonpolar tails face each other)
• Contains integral (embedded in the membrane) and peripheral proteins
(found on the inner membrane surface)
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Plasma membrane
ØFunction
• Separates cell contents from environment
• Serves as a diffusion barrier
!
Regulation of transport by Passive transport includes
!
Diffusion (“Osmosis” and “Dialysis”) or Active transport
• Detection of signals
• Cell-cell communication
• Cell identity
• Helps in cell movement
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The major intracellular compartments of cell:
“Organelles”
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Animal Cell Organelles
Nucleus
Ø Structure
I. Nuclear envelope
* Composed of inner
and outer membrane
separated by
perinuclear space
* Has nuclear pores
which connect with ER
II. Nucleoplasm
* Fluid of the nucleus
III. Nucleolus
* Not separated by
membrane
* is area of formation of
ribosomal RNA,
* is area of condensed
DNA and chromatin
DNA is tightly packaged up into nucleus!
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Animal Cell Organelles
Nucleus
“contains the genetic information of the cell”
Ø Function
* Storage of genetic material (DNA)
* Production of messenger RNA and
ribosomes that needed for protein
synthesis.
* Storage of proteins and RNA in the
nucleolus.
* During the cell division, chromatins
are arranged into chromosomes in the
nucleus.
* Function in selective transportation
of regulatory factors and energy
molecules through nuclear pores.
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Animal Cell Organelles
Mitochondria
“ Energy producing organelle”
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Animal Cell Organelles
Mitochondria
Ø Structure
• Surrounded by 2 membranes:
- smooth outer membrane (permeable)
- folded inner membrane (impermeable)
with layers called “cristae”
• Contain two internal compartments:
- mitochondrial matrix is within the
inner membrane (contain ribosomes
mitochondrial DNA (mtDNA) and
enyzmes)
- intermembrane space is located
between the two membranes
mtDNA:
The structure of mitochondria.
Ref:microbewiki.kenyon.edu/index.php/
Mitochondria
Cell Structure & Tumor Microenvironment
• inherited from mother
• not protected by histones
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Animal Cell Organelles
Mitochondria
Function: Oxidative phosphorylation”--ATP synthesis
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Animal Cell Organelles
Mitochondria
Function: Reactive Oxygen Species (ROS)/ Free radical generation
Ref: Murphy MP. Biochem J, 2009
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Animal Cell Organelles
Mitochondria
Function: Regulation of apoptotic death and cell growth
Apaf-1: Apoptotic
protease activating
factor 1
Ref: http://www.reading.ac.uk/nitricoxide/intro/apoptosis/mito.htm
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Animal Cell Organelles
Endoplasmic reticulum (ER)
“cell’s internal membrane system”
Ø Structure
Cisternae
• Cisternae (sac-like structures)
• Cisternal space (or lumen)
• ER membrane is
continuous with nuclear
envelope
Ø Types of ER
• Smooth-type (SER) :
•Ribosome-free
•Contains enzyme for lipid
biosynthesis
•Involved in attachment of
receptors on cell membrane
proteins
• Rough-type (RER) :
•Ribosomes embedded in
surface
•Involved in protein
synthesis
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Animal Cell Organelles
Endoplasmic reticulum (ER)
ØFunction
• Protein folding, modification and secretion
• Cellular protein quality control by extracting and degrading
unfolded proteins (known as a ER-associated protein
degradation-ERAD)
• Lipid and sterol biosynthesis
• Storage of calcium ions in the ER lumen and their regulated
release into the cytosol (calcium homeostasis)
• Detoxification of drugs
• Core oligosaccharide biosynthesis
• Apoptosis
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Major responses to ER stress
http://www.pdbj.org/eprots/index_en.cgi?PDB%3A2RIO
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Animal Cell Organelles
Golgi Apparatus
Ø Structure
• is made up numerous group of
flat membranes called cisternea
forming a sac
Cisternea:
* a complex network of tubules and
vesicles are located at the edges of
cisternea
•help proteins and cytoplasmic
components travel between different
parts of the cell
• has three regions:
--- Cis face (near to ER)
Receive transport vesicles from
ER
--- Trans face (far away from ER)
Packages the material in vesicles and send outside of Golgi
--- Golgi stack (between these two region)
Main processing area
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Animal Cell Organelles
ØFunction
Golgi Apparatus
• Receives, sorts,
modifies, packs and
ships the proteins
• Produce membrane
packages called vesicles
• Protects cells from
apoptosis
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Animal Cell Organelles
Ø Structure
Lysosomes
• are membrane enclosed vesicles
(spherical bodies about 50-70 nm in diameter)
• arise from the golgi apparatus
• are found in all animal cells such as
white blood cells.
• contain hydrolytic enzymes that digest
& destroy macromolecules
• two types of lysosomes:
--- Peroxisomes: catalases & oxidases
--- Proteosomes: proteases- cathepsin
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Animal Cell Organelles
Lysosomes-“suicide bags” and “recycling”
Ø Function
•Destroy invading bacteria or viruses (Phagocytosis)
•Degrade older or damaged organelles (Autophagy)
•Degrade macromolecules (Endocytosis)
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Cytoskeleton
“the movers and shapers in the cell”
is found underlying the cell membrane in the cytoplasm
Major Structures of the Cytoskeleton
I. Actin filaments (or Microfilament)
Microfilament structure and assembly
http://micro.magnet.fsu.edu/cells/microfilaments/microfilaments.html
* occur in every cell
* composed of polymerased actin proteins
* interact specifically with myosin helical polymers made of actin flexible,
organized into 2D networks and 3D gels
* function in cell movement and cellular contraction
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Major Structures of the Cytoskeleton
II. Microtubules
Microtubule helical structure
http://micro.magnet.fsu.edu/cells/microfilaments/microfilaments.html
III. Intermediate filaments
* composed of polymerased alpha
and beta-tubulin
* rigid, long, straight, holo tupe
* length: 200 nm-25 µm
* are used for centrioles
•structural support of Cilia and
Flagella
•Involved in the movement of the
materials within the cells
* occur only in animal cells
* composed of polymerased
keratin proteins
* rope-like structure
* size: 8 -12 nm
* provide structural stability
Intermediate filament structure
http://micro.magnet.fsu.edu/cells/microfilaments/microfilaments.html
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Cytoskeleton
http://ccaoscience.wordpress.com/notes/protein-structureswithin-the-cell/
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Function
* Cell shape,
* Cell polarity
* Cell movement:
-muscle contraction via
actin filaments and
myosin proteins
-Flagella
-Cilia
* Cell cycle:
Cell division and
chromosomal separation
by actin and tubulin
cytoskeletal structures
* Cell adhesion
* Phagocytosis (by actin
filaments)
* Wound healing
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Extracellular matrix (ECM)
is the defining feature of connective tissue in animals
Epithelial cells
Basement membrane
Endothelium lining
the capillary
Connective tissue with
Interstitial matrix
Fibroblasts
•
•
•
http://en.wikipedia.org/wiki/
Extracellular_matrix
is made up of Adhesive glycoproteins (fibronectin and laminin),
Structural proteins (collagen and elastin) and Polysaccharides
(glycosaminoglycans, proteoglycans)
includes the interstitial matrix and basement membrane
consisting of various cell types (i.e. fibroblasts, epithelial cells) and
secreted proteins (cytokines)
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Extracellular matrix (ECM)
Ø Function
• Cell shape,
• Cell attachment,
• Adhesion,
• Migration (example: wound healing),
• Cell proliferation,
• Polarity,
• Differentiation,
• Survival & apoptosis,
• Motility,
• Management of growth factors,
• Embryonic development.
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Apical
Epithelial Cells
&
Mesenchymal cells
Lateral
Basal
• are polygonal in shape
• have three membrane
domains: apical, lateral and
basal,
• have adherens junctions
• have tight junctions between
apical and lateral domains,
• express cell-cell adhesion
markers such as E-cadherin,
• lack of mobility.
Cell Structure & Tumor Microenvironment
• are fairly uniform small spindleshaped cells,
• do not make mature cell-cell
contacts, and can invade
through the ECM,
• are connected to other cells
within a 3D- cellular network,
• bipolar
• express markers such as Ncadherin, Twist, snail, fibronectin
• can migrate easily
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Epithelial-mesenchymal transition (EMT)
• is characterized by loss of E-cadherin, disruption of cell
adhesion, and induction of cell motility and invasion to convert a
mesenchymal phenotype
• function in embryonic development, organ formation, tissue
regeneration, wound healing, organ fibrosis and cancer
progression and metastasis.
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Cell-cell adhesion
Cadherins
Homotypic cell adhesion by
• are transmembrane proteins
• mediate Ca+2-dependent cell- E-cadherin within the epithelium.
cell adhesion
• interact in a zipper-like fashion
• stabilized by catenin complex
• are cell type specific
Several types of cadherins:
* E-cadherin (epithelial)
* P-cadherin (placental)
* N-cadherin (neuronal)
(Ref: Mohamet et al., Journal of Oncology, 2011)
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Cell-cell adhesion
“intercellular junctions”
Plasma
membrane
Intracellular
space
Tight junction
proteins
Tight
junction
Plasma
membrane
Protein
filaments
Intercellular
plaques
Intracellular
space
Desmosome
Intracellular
space
Plasma
membrane
Protein
channels
Connexons
Gap
junction
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Cell Structure & Tumor Microenvironment
• Tight junction:
- fused membranes of adjacent cells
- form a continuous belt around cells
- impermeable
- ex: intestine, kidneys, bladder,
epithelium of skin
• Desmosomes
- fastening adjacent cells together
by connecting cell membrane to
cytoskeleton proteins
- binding spots between cells with
cadherins
-ex: skin, heart
• Gap junction
-Transmembrane proteins called
connexons joint together to make a
channel.
- allow small molecules to pass
directly from cell to cell
-ex: heart muscle, animal embryos.
(in heart muscle, the flow of ions
through gap junctions coordinates
the contraction)
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Cell-ECM adhesion
Cell adhesion molecules-”Integrins”
• are transmembrane heterodimeric cell-surface molecules
• are receptors for ECM
• are concentrated in cell at specific zone called Focal adhesions
• are important for adhesion to ECM and transmembrane signaling
• function as a link between ECM and the actin cytoskeleton
• are important for cell growth
The regulation of the extracellular binding activity of a cell's integrins Ref: Molecular Biology of the Cell, 4th edition
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Tumor types
Bening (non-cancerous) tumor vs malignant (cancerous) tumor
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Tumors as 'wounds that do not heal'
Normal skin tissue
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Invasive carcinoma
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Cancer classifications
Based on the location or origin of the malignant tumor
Carcinoma
Malignant tumors
of epithelial cells
Sarcoma
Lymphoma
Malignant tumors
Malignant tumors
of lymphocytes
of supporting tissue
(non-epithelial tumors:
mesenchymal origin)
Solid tumor
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Leukemia
Malignant tumors
of blood cells
Non-solid tumor
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Normal Cells vs Cancer Cells
Microscopic appearance of
cancer cells
Mammary gland
http://www.gfmer.ch/
selected_images_v2/detail_list.php?
cat1=2&cat2=8&cat3=0&cat4=3&styp
e=n
Mammary carcinoma
http://www.hindawi.com/
journals/ijol/2011/187623/fig1/
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Common characteristics of cancer cells
• Uncontrolled cellular proliferation
• Unbalanced cell division
• Loss of apoptosis
• Loss of special function (abnormal organelles and cell
components and high rate of differentiation)
• Abnormal vessel wall structure
• Tissue invasion & metastasis
• Angiogenesis
• High glycolytic rate
• Hypoxia
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Nuclear structure in cancer cells
Normal
N
e
ucl
oli
Nuclear Nuclear
lamina matrix
PML
CancercPoerinuc
mp
leo
artm
la
ent r
PML: Promyelocytic
leukaemia
NMP: nuclear matrix
proteins
NMP
(Ref: Zink et al.,
Nature reviews, 2004)
heterochromatin
• Single and small nucleus &
nucleolus
• Fine chromatin granules in the
nucleus
• Clear nuclein stain
• The smooth nuclear boarder
• Stain artifact in one cell where
another small white blood cell
overlaps.
Cell Structure & Tumor Microenvironment
• Multiple and large nucleolus & nuclei
• Large chromatin clumps in the
nucleus
• The dark staining of the nucleus and
irregular nuclear boarder.
• Nuclei can become irregular and
begin to fold
• PML bodies can mislocalized.
• Specific NMPs are absent
• Perinuclear compartment is present
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Mitochondria in cancer cells
• mtDNA mutations inhibit oxidative phosphorylation: Increase ROS level and tumor
cell proliferation
Apoptosis-resistant mitochondria and cancer
Ref: Indran et al., BBA, 2011
mitochondrial membrane permeabilization (MMP)
permeability transition pore complex (PTPC)
HKII: hexokinase II
•Crosstalk between nucleus and mitochondria contribute to oncogenesis and
tumor progression
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UPR & ER stress in cancer cells
http://www.hindawi.com/isrn/cell.biology/2013/256404/fig1/
Ref: Wang et al., Am J Transl Res, 2010
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Lysosome alterations & Autophagy in cancer cells
Normal
Cancer
Lysosomes in normal versus cancer cells.
Visualization of the lysosomal compartment
(using lysosome-associated membrane
protein 1) monoclonal
antibodies, red) and the actin cytoskeleton
(using anti-β-actin monoclonal antibodies,
green) in murine embryonic fibroblasts.
Note the perinuclear and peripheral
localization of lysosomes in control and
transformed cells, respectively.
Defects in lysosome increase expression
and altered trafficking of lysosomal
enzymes participates in tissue invasion,
angiogenesis and lysosomal death
pathway.
Autophagy act as both a “tumor suppressor”
by preventing the accumulation of damaged
proteins and organelles and as a “mechanism
of cell survival” that can promote the growth of
established tumors.
Ref: Kroemer and Jäättelä nature Reviews, 2005, 5:
886-897
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Plasma membrane structure in cancer cells
Komizu et al,
Changes in the plasma membrane fluidity of tumor cells may affect antigens and
receptors as well as the cancer cell motility and capacity to infiltrate the basement
membrane and the deformability potential of metastatic cells.
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Cytoskeletons in the cancer cells
Actin cytoskeleton in the invasion/ metastatic process
Vignjevic and Montagnac, Seminars in Cancer Biology, 2008
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Integrins and cadherins in the cancer cells
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EMT in Tumor Progression
Progression
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Normal stroma vs tumor microenvironment
(Zhang and Liu, Pharmacology and Therapeutics 137(2), 2013
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The tumor microenvironment
• Neoplastic cells: i.e. cancer stem cells, cancer associated fibroblast,
• Infiltrating cells: i.e. lymphocyte, macrophage,
• Resident cells: i.e. fibroblasts, endothelial cells,
• Secreted soluble factors
Cytokines (i.e. CXCR-4 and CXCL-12, TNF-α),
Matrix-altering enzymes” (i.e. matrix metalloproteinases (MMPs))
Growth factors
VEGF: Vascular endothelial growth factor,
FDG: Fibroblast growth factors
PDGF: The platelet derived growth factor
TGF-β: Transforming growth factor beta
• The extracellular matrix
• Hypoxia (low oxygen levels)
• Acidic conditions (low pH level)
• Hypoglycemia (low glucose level)
• Massive cell death
• Abnormal properties of surrounding cells
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Hypoxia in solid tumor
•
Imbalance between
oxygen supply and
oxygen consumption in
tumors
B
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Hypoxia-induced angiogenesis
A
Molecular mechanisms of tumor-associated angiogenesis. (Ref: Simpson-Haidaris
et al., PPAR Research, 2010)
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Blood vessels & flow in cancer cells
Diagrammatic representation of the vascular system. A. Normal tissue. B. Solid tumor. Red represents well-oxygenated
arterial blood, blue represents poorly oxygenated venous blood, and green represents lymphatic vessels. (Ref: Tredan et al.,
JNCI, 2007, 99:1441-1454)
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Tumor-associated angiogenesis in tumor microenvironment
A
B
Tumor-associated angiogenesis is sustained through stromal microenvironment crosstalk.
(Ref: Simpson-Haidaris et al., PPAR Research, 2010)
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Metalloproteinases (MMPs)
• are metal-dependent endopeptidases
• are produced by stromal cells rather than by tumor cells in many solid
tumors
Ref: Roy et al., JCO, 2009
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Hypoxia-induced EMT in tumor microenvironment
Various factors that induce cancer cell EMT in tumor microenvironment. (Ref: Jing et al., Cell & Bioscience 2011, 1:29)
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Cancer stem cells
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Fibroblasts
• are principal cellular component of connective tissue
• synthesize ECM and collagen
• are involved in the production & remodeling of the ECM
• provide potentially oncogenic signals such as TGF-β and
hepatocyte growth factor (HGF) to resident epithelia
• stimulate cancer-cell proliferation and invasion by secreting growth
factors such as TGF-β and stromal-cell-derived factor 1 (SDF1).
NIH/3T3 Fibroblasts in cell culture
(Ref: http://en.wikipedia.org/wiki/Fibroblast)
Tumor Associated Fibroblasts
Fibroblast
Cell Structure & Tumor Microenvironment
Tumor associated fibroblast
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Endothelial cells & Pericytes
Pericytes are adjacent to endothelial cells and embedded within
the vascular basement membrane of blood microvessels.
They participate in the construction of the tumor-associated
vasculature
Endothelial–pericyte interactions in microvessels
EC
Ref: Armulik et al., Circulation
Research, 2005
Pericytes - Endothelial
cells signaling network
can contribute to tumor
development and
metastasis
Tumor-associated endothelial cells
Function in tumor development, progression and metastasis
formation and
Angiogenesis/ lymphangiogenesis)
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Immune inflammatory cells
Many tumor-associated immune cells such as macrophages, dendritic
cells, and cytotoxic T cells may either promote tumor growth and
progression or protect the cancer cell from apoptosis
Macrophages
• are white blood cells
• are crucial member of tumor stromal cells.
• are phagocyte of cell debris and pathogens
• function in wound healing, inflammatory
response
Tumor associated macrophages
•
•
•
•
http://legacy.owensboro.kctcs.edu/gcaplan/
anat/histology/api%20histo
%20connective.htm
induce tumor growth,
promote angiogenesis,
enhancement of tumor cell migration and invasion,
promote metastasis
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Adipocytes
• are in mammary gland and bone marrow
• act as a energy source for the normal and cancer cells
• secrete hormons, growth factors, MMPs and specific
cytokines (i.e. adipokines, adiponectin, resistin, visfatin)
• primarily constitute adipose tissue
• are involved in tumor progression
Section of tumor (mauve) in the
presence of adipocytes (white discs).
The arrows indicate adipocytes
modified by the tumor.
(Credit: Copyright G. Escourrou)
Cell Structure & Tumor Microenvironment
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Communication of tumor cells with tumor
microenvironment
Intravasation
Cell Structure & Tumor Microenvironment
Ref: Sun et al., Cancer Metastatis Rev. 2010
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SDF-1 & CXCR4 in Tumor microenvironment
.
EPCs: Endothelial progenitor cells
Ref: Orimo and Weinberg (2006)
stromal cell derived factor-SDF-1 (CXCL12)
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Organ-spesific metastasis & tumor microenvironment
..
Ref: Sun et al., Cancer Metastatis Rev. 2010
Cell Structure & Tumor Microenvironment
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Transforming growth factor beta (TGF-β) in cross talk
Cell Structure & Tumor Microenvironment
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TGF-β and SDF-1 autocrine signaling in myofibroblast formation
(Ref: Kojima et al., PNAS 2010, 107(46): 20009–20014)
Cell Structure & Tumor Microenvironment
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Hedgehog signaling
Basal cell
carcinoma
Normal
(Smoothened)
(The Suppresor
of Fused)
Patched domaincontaining protein
Ref: Epstein, Nature Reviews Cancer 8, 2008
Cell Structure & Tumor Microenvironment
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Hedgehog signaling in tumor microenvironment
Ref: Curran & Ng, Nature 455, 2008
Cell Structure & Tumor Microenvironment
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Heterotypic interactions as therapeutic targeting
“Targeting the tumor microenvironment”
chemokine inhibitors)
Inh
VE ibito
sig GF, Frs of
nal
ing GF
Cell Structure & Tumor Microenvironment
Inhibitors of
HGF /c-Met
Inhi
PDGbitors o
f
sign F
aling
Anti-inflammatory
inhibitors (cytokine,
Inh
ma ibito
trix rs o
tur f
no
ver
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QUESTIONS?????
[email protected]
Cell Structure & Tumor Microenvironment
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