EMT in cancer

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					       EMT and Cancer

Subtitle: Be Good to your Cadherins
           Epithelial Cells                     Mesenchymal Cells:
Junctions Complex, stable                       Looser or none
Tissue    Uniform array, continuous layer       No uniform tissue structure
Polarity Apical vs. Basal                       Leading vs. Trailing edge
Motility Lack of mobility by individual cells   Motile, potentially invasive
                Adhesion




MDCK                  NIH3T3
   Strong, stable          Loose, transient
  E-cadherin based         N-cadherin based
                 Polarity




Columnar Epithelium         Migrating Fibroblast
                                               Motility




Lecuit & Pilot, Nature Cell Biology 5, 103 - 108 (2003)
                        What is EMT?
EMT in Development
  • Implies a comprehensive and coordinated change of fate and/or
       function.

EMT in the Adult
  • What is it?
       • Loss of E-cadherin
       • Increased migratory/invasive behavior
       • Loss of Epithelial characteristics
       • Fibroblastoid Morphology
   • Does it exist?
       • Depends on your definition
       • Mixed lineage markers
   •Where is it important?
      • Wound Repair
       • Fibrosis
       • Metastasis
Steps in Malignant Progression
                           Metastasis




                Metastatic Growth in the Liver
• > 90% human cancer is epithelial in origin
• Metastasis-associated tumorigenesis accounts for 90% of cancer deaths
       Functional Definition of EMT




1. Complete EMT
   A process wherein static epithelial cells:
       1. Loose cell-cell contacts
       2. Acquire mesenchymal morphology
       3. Manifest a migratory phenotype
       4. Increases in extracellular proteolytic activity
       5. Proliferative
2. Incomplete EMT
       A transition involving less then the complete set, but still
       may have significant ramifications on the functioning of the
       cell population.




  Virtually all carcinomas will retain significant expression of
 epithelial markers, while simultaneously losing key epithelial
 determinants and inappropriately expressing mesenchymal
 markers, so EMT-like may be a better term.
       Molecular Definition/Signature of EMT
Proteins that decrease in abundance        Proteins that increase in abundance
  E-cadherin                                 N-cadherin
  Desmoplakin
  Cytokeratin                                Snail1 (Snail)
  Occludin                                   Snail2 (Slug)
                                             Twist
 Proteins whose activity increases
   Rho                                       MMP-2
   GSK-3fl                                    MMP-3
                                             MMP-9
 Proteins that accumulate in the nucleus
                                             Vimentin
   Smad-2/3
                                             Integrin {alpha}vfl6
   Snail1 (Snail)
                                             Fibronectin
   Snail2 (Slug)
                                             Goosecoid
   Twist
                                             FOXC2
   fl-catenin
                                             Sox10
   NF-{kappa}fl
                                                                       Extracellular
                                                               Ca 2+
                                                                          Space
 Wnt
                                      E-Cadherin
                                                               P
         Frz II
                                 b-catenin
                                                          p120

                              a-catenin
         APC          Dsh
Axin

                                                      actin
                                                   filaments
 Gsk3b
                  P




                            Tcf/Lef
Cadherins as Master Regulators of Morphology
• Focus is often on adhesive function: Cadherins as molecular glue
                                 Passive Inhibition
  AJ’s                           Rho-GTPases
                                                         CDKI: p27/p21
  Type of Cadherin               Active Promoter
                                                         Wnt
  Stabilize others junctions        Motility
          Adhesion                                    Proliferation


                                Cadherins
         Receptor                                     Actin Cytoskeleton
         Signaling             Transcriptional/
                                                         a-catenin
    EGF                         Nuclear Role
                                                         Rho-GTPases
    FGF                        b-catenin/Wnt             Arp2/3
    PDGF                       P120/kaiso
                               In nucleus
                     E-Cadherin Expression Levels are critical for Morphology
Normal




                                 p120                  E-cad               Overlay
Ulcerative Colitis




                                 p120                  E-cad               Overlay
          E-cadherin Loss/Downregulation

1. Mutation
    - Seen in gastric carcinoma and lobular breast cancer
2. Post-transcriptional down-regulation
   -   Hakai, p120-dependency


3. Promoter methylation
4. Transcriptional Repression
E-cadherin Transcriptional Repression
   Wnt
  BMP
  Notch

                          Bind E-box
        Is loss of E-cadherin enough?
Probably not
   • Concomitant production of Mesenchymal Cadeherins
   • Other effects of Snail/Slug Twist




          Barrallo-Gimeno, A. et al. Development 2005;132:3151-3161
Is EMT required for cancer metastasis?
   Numerous pathological studies have found sites of
metastases which appear as well differentiated epithelium




     Christiansen, J. J. et al. Cancer Res 2006;66:8319-8326
       Molecular Definition/Signature of EMT
Proteins that decrease in abundance        Proteins that increase in abundance
  E-cadherin                                 N-cadherin
  Desmoplakin
  Cytokeratin                                Snail1 (Snail)
  Occludin                                   Snail2 (Slug)
                                             Twist
 Proteins whose activity increases
   Rho                                       MMP-2
   GSK-3fl                                    MMP-3
                                             MMP-9
 Proteins that accumulate in the nucleus
                                             Vimentin
   Smad-2/3
                                             Integrin {alpha}vfl6
   Snail1 (Snail)
                                             Fibronectin
   Snail2 (Slug)
                                             Goosecoid
   Twist
                                             FOXC2
   fl-catenin
                                             Sox10
   NF-{kappa}fl
Why such diversity in the EMT profile in Cancer?
   Development
      • EMT is generated through a concerted and
         regulated transcriptionally-driven process

   Cancer
      • EMT is generated through a wide array of
          mutations, epigenetic events, and inappropriate
          signaling
      • Furthermore, selective pressures stemming from
      competition for limited resources leads to clonal
      expansion increasingly fit clonal populations
  Clonal Evolution of Cancer




Greaves, The Lancet, Volume 3, Issue 4 , April 2002, Pages 244-251
Why such diversity in the EMT profile in Cancer?
   Development
      • EMT is generated through a concerted and
         regulated transcriptionally-driven process
   Cancer
     • EMT is generated through a wide array of
         mutations, epigenetic events, and inappropriate
         signaling
     • Furthermore, selective pressures stemming from
     competition for limited resources leads to clonal
     expansion increasingly fit clonal populations

      Together these contribute to a large number of
      potential molecular profiles leading to the diversity
      observed in malignancies

				
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posted:10/10/2011
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