epithelial mesenchymal transitions (emt) in cancer metastasis greg longmore, february 19, 2008
TRANSCRIPT
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Epithelial Mesenchymal Transitions (EMT)In Cancer Metastasis
Greg Longmore, February 19, 2008
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Post-Transcriptional Regulation of Snail/EMT
1. A. Cano et al., Nat. Cell Biol. 2:76-83, 2000 2. B.P. Zhou et al., Nat. Cell Biol. 6:931-40, 20043. Z. Yang et al., Cancer Res. 65:3179-84, 20054. H. Peinado et al., EMBO J. 24:3446-58, 20055. J.I. Yok et al., Nat. Cell Biol. 8:1389-406, 2006 6. E. Langer et al., Dev. Cell March 11, 2008
Reviews
1. J.P. Thiery and J.P. Sleeman Nature Rev. Mol. Cell Biol. 7:131-142, 2006 2. H. Peinado et al., Nature Rev. Cancer 7:415-428, 2007 3. A. Barrallo-Gimeno and M.A. Nieto. Development 132:3150-61, 20054. J.P. Thiery. Nature Rev. Cancer 2:442-54, 2002
Breast Cancer
1. S.E. Moody et al., Cancer Cell 8:197-209, 20052. N. Fujita et al., Cell 113:207-19, 20033. C. Xue et al., Cancer Res. 63:3386-94, 20034. A. Dhasarathy et al., Mol. Endocrinology 21:2907-18, 2007
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1. Cancer Metastasis
2. EMT - MET - definitions
3. In Normal Development 4. In Adult Pathology
5. Signals that Induce EMT
6. Snail Family - Transcriptional regulators of EMT
7. Clinical - Breast Cancer
OUTLINE
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1. Primary tumors (10%) rarely kill, metastases do (90%)
2. Primary tumor size often predicts for metastasis
3. Some tumors don’t metastasize (skin SCC, brain glioblastoma) while other do frequently (melanoma)
4. Some tumors have a propensity for specific tissue metastasis(breast, prostate - bone), while others are excluding from tissues
- when considering blood flow as a single variable
5. “micrometastases” at diagnosis - breast, colon - worse outcomes
6. Organ fibrosis is a significant risk factor for the development ofaggressive cancers (hepatic cirrhosis, lung fibrosis)
7. The metastatic process (Fig.)
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Cancer Metastasis
INVASIONEMT
MET
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EMT in DevelopmentGastrulation Neural Crest Delamination
Epithelial Mesenchymal
EMT in the Adult
- epithelia wound healing (skin)- tissue fibrosis in response to injury (lung, kidney, liver)- epithelial cancer metastasis
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Skin wound healingSlug expression
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Epithelial Mesenchymal Transition (EMT)
Altered Cell Morphology
Breakdown of Intercellular Junctions
Increased Cell Motility / Invasiveness
Mesenchymal Epithelial Transition (MET)
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Lost or decreased1. Epithelial adhesion receptors - E-cadherin, Occludin, Claudins2. -catenin, -catenin frequently translocates to nucleus (Wnt) 3. Circumferential F-actin fibers4. Epithelial cytokeratins5. Apico-basal polarity
Acquired1. Intermediate filament protein - Vimentin2. Matrix metalloproteinases secreted, produced 3. Fibronectin secretion4. N-cadherin5. -smooth muscle actin (myofibroblasts)6. v6 integrin7. Motility, Invasiveness
Cellular changes during EMT
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Tight junctionAdherens junction
Gap junctionDesmosome
Apical Surface
focal adhesions
Basolateral Surface
Epithelial Cells
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Epithelial cell-cell adhesive complexes: general organization
Adherens Junctions: Cadherins - catenins - Actin
transmembrane receptor
cytoplasmic plaque proteins“scaffolding / adapter proteins”
Cytoskeletal elements
outside
inside
signal
transduction
polarityproliferation
cell fate
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E-cadherin and Cancer pathogenesis“A metastasis tumor suppressor gene?”
1. Mouse models - TAG-insulinomas2. Germline mutations in CDH1 strongly predispose individuals to
gastric cancer and breast cancer3. Somatic inactivating mutations in CDH1 in gastric cancers and
infiltrative lobular breast cancers
4. But in the majority of cancers where CDH1 expression is lostmutations are rare or absent
(? Epigenetics or trans-acting factors)
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E-cadherin (brown)
Colon Cancer
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transformedhuman mammary cells
implanted in amouse
Does EMT occur in vivo?
Lung Fibrosis model: - -gal transgenic mice + TGFgenerate-gal + myofibroblasts
PyV-mT, FSP1.TK mice - less invasion and Metastasis following treatment with GCV
Other Data
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Extrinsic Signals that Induce EMT:
- Tumor-derived (autocrine), Stromal Cell-derived (paracrine) - FGF, TGF-, EGF, HGF (scatter factor), Wnt, TNF- - E-cadherin cleavage (MMPs)- E-cadherin endocytosis
Intracellular Pathways:
- PI3K - Ras - MAPK, - GSK3, NF-B, p38, Smads, STAT3- Rac1b - ROS (MMP-3)
Transcriptional regulation:
- E2a/E47, FOXC2, SIP1, Snail, Slug, Twist
SIGNALING
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QuickTime™ and a decompressor
are needed to see this picture.
+ Snail
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The Snail family of transcriptional repressors
Snail 264aa
Slug 269aa
SNAG Domain Zinc Fingers
Scratch 348aa
Smuc 292aa
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Snail or Slug
FGF
Neural crestGastrulationLimb dev’pt
Tumor metastasis
Wnt
Neural crestHeart dev’pt
Tumor metastasis
TGFSkin
Palate fusionTissue fibrosisHeart dev’pt
Tumor metastasis
BMP
Neural crestL/R asymmetry
Mammary dev’ptgastrulation
Tumor metastasis
EGF
GSK3-mediatedphosphorylation
MTA3
Estrogens
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BUT, There is only a modest inverse relationship between
Snail and E-cadherin expression (IHC, mRNA) in many metastatic cancers
With possibly one exception - breast cancer (see later)
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SNAG Domain
Zinc Fingers
93 - SDEDSGKGSQPPSPPSPAPSSFSSTSVSSLE- 122
GSK3 nuclear export
GSK3cytoplasmicdestruction
S246
Pak1
K98 K137
LOX 2/3
Ajuba LIM proteins:- adapters that assemble
repressor complex (co-repressors)
Snail Modification/Function
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QuickTime™ and aTIFF (Uncompressed) decompressor
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Inhibit GSK3 - increase Snail - decrease E-cadherin - metastasis
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QuickTime™ and a decompressor
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QuickTime™ and a decompressor
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Wnt - Axin2(mRNA) - GSK3 nuclear-cytoplasm - Snail nuclear - EMT/Invasion
How a Wnt signal cooperates with Snail to influence metastasis
Remember Wnt also inhibits GSK3 - stabilizes Snail, and - results in nuclear translocation of -catenin
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EpithelialMarkers
E-cadherinClaudinsOccludins
DesmoplakinCytokeratins
Mesenchymalmarkers
FibronectinVitronectinVimentin
Cell shape changesCell movements, invasion
RhoBMMPs
Proliferation
Cyclin DCDK4
Rb phosphp21
Survival
PI3K activityERK activityCaspases
P53BID
Snail or Slug functions