Docstoc

C-Met Receptor

Document Sample
C-Met Receptor Powered By Docstoc
					The c-Met receptor contributes to motility
     and invasion in high grade STS;
      a potential therapeutic target

  Sarah E. Myers, Theresa G. Nguyen, Quan-Sheng Zhu,
  Alexander J.F. Lazar, Raphael E. Pollock, Dina C. Lev


            Presented by Gonzalo Lopez, MS

             Sarcoma Research Laboratory
              MD Anderson Cancer Center
                    Houston, TX
Sarcomas are heterogeneous

   • Complex karyotype:

      Leiomyosarcoma
      MFH/UPS
      MPNST

   • Generally poor prognosis
Migration and invasion critical for STS metastasis
                         Proliferation/          Migration
    Primary tumor        angiogenesis            /invasion           Embolism/circulation




                             Adherence to                                Transport
                                                Arrest in organs
     Extravasation            vessel wall




          Establishment        Proliferation/
     of a microenvironment     angiogenesis
                                                                   Metastasis




   What are the molecular drivers of these processes???
           Candidate mechanisms:
       receptor tyrosine kinases (RTK)

• RTKs: c-Met, EGFR, VEGFR, c-Kit, etc.
• RTKs: central components of signaling networks
  (embryogenesis, cell proliferation, apoptosis)
• RTK deregulation: diabetes, developmental defects,
  and cancer
• Activated RTKs: induce pathways of cell migration
  and invasion
     c-Met receptor: relevant biology

•   Found in mesenchymal and epithelial tissues

•   Ligand HGF (hepatocyte growth factor)

•   Involved in embryogenesis, wound healing

•   Broad range of downstream effects
c-Met receptor




       WG Jiang et al. 2005
              Experimental goal

To evaluate the impact of c-Met activation and inhibition
on complex karyotype STS migration and invasion
c-Met is expressed in human STS tissue




                   Leiomyo/UPS TMA




                       MPNST TMA
                            HGF




                            Total c-Met




                            Phospho c-Met

Phosphorylated c-Met correlates with dismal outcome
                (HR 2.32; p=0.012)
c-Met is expressed in human STS cell lines




                                              c-Met

                                              -actin

          HT1080   SKLMS1   A204
    HGF   -   +    -   +    -   +
                                    p c-Met
                                    c-Met
Birchmeier,C. Nature Reviews. 2003
HGF activates ERK and AKT

       SKLMS1   A204
 HGF   - + -      +
                       p c-Met

                       c-Met
                       p ERK
                       ERK
                       p AKT

                       AKT
                       β-actin
                            HGF induces migration
                                                    SKLMS1

                                                    HGF (-)
Avg. # of cells/HPF




                                                    HGF (+)




                      HGF    -        +     -          +
                                 SKLMS1         A204
                      HGF induces invasion

                                             SKLMS1

                                             HGF (-)
Avg. # of cells/HPF




                                             HGF (+)




HGF                   -        +     -          +
                          SKLMS1         A204
            Inhibition of c-Met


• Small molecule inhibitor (PHA-665752, Pfizer)

• Anti c-Met siRNA
  PHA inhibits c-Met activation
   and downstream signaling


PHA   -   -   +     +   +
HGF   -   +   +     +   +
                             p c-Met

                             c-Met

                             pERK

                             ERK

                             pAKT
                             AKT
c-Met siRNA effect on downstream signaling
          Mock        NT       siRNA
    HGF   -   +   -        +   -   +
                                       p c-Met

                                       c-Met

                                       pERK

                                       ERK

                                       pAKT

                                       AKT
c-Met blockade abrogates HGF induced invasion



                              DMSO    DMSO + HGF   PHA         PHA + HGF
  Avg. # of cells/HPF




                        HGF      -          +            -         +
                                     DMSO                    PHA
HGF induces migration and invasion genes
                             HGF
 - HGF       + HGF
                             -   +
                                     FN1


                     FN1             ITGB5

                     ITGB5           LAMB1
                     LAMB1

                     LAMA5           LAMA5
                     MMP2

                                     MMP2

                                     GAPDH
                     Conclusions
•   Human STS samples highly express c-Met, HGF, and
    activated c-Met

•   Activated c-Met expression correlates with dismal
    outcome in MPNST

•   Activation of c-Met receptor on STS induces
    migration and invasion

•   c-Met blockade abrogates these processes
           Acknowledgements

• Sarcoma Research Laboratory at UTMDACC

      Dina C. Lev, MD
      Raphael E. Pollock, MD/PhD
      Alex J.F. Lazar, MD/PhD
      Sarah E. Myers, BS
      Wenhong Ren, MD
      Colleagues and Staff

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:10
posted:11/10/2011
language:English
pages:22