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Molecular basis of oncogenic transformation and signaling pathways

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Molecular basis of oncogenic transformation and signaling pathways Powered By Docstoc
					Molecular basis of oncogenic
transformation and signaling
         pathways

           Path 822
        October 6, 2005

        Bruce Elliott
Age-standardized incidence rates for selected cancer sites
             (Females, Canada, 1970-2004)


        • 1 in 8 women in their lifetime will be diagnosed
         with breast cancer.

        • 1 in 3 will die of metastasis.




                                                             NCIC
                                                             Statistics
                                                             (Cancer.ca)
Clonal evolution of cancer
• Nowell’s Hypothesis
•Vogelstein Model of tumor progression




                 Volgelstein, et al. Nat Rev Cancer. 2003 Sep;3(9):695-701.
Characteristics of normal epithelium
   • Polarity
   • Adhesion to basement membrane
   • Transition from basal (stem) cells to
   differentiated cells (transitional
   epithelium)
   • cell-cell contacts
Cell-cell contacts

1. Adherens junctions

2. Tight junctions

3. Desmosomes

4. Gap junctions
            microvilli


           tight junction
Junctional
Complex adhesion belt                                      cadherins
           desmosome



       keratin filaments

         gap junctions


              

                         hemidesmosome basal lamina
                                                      rd
Mammary tumor progression
 Normal              DCIS




          Invasive
     Epithelial-mesenchymal transition

                   - E-cadherin

                   +E-cadherin


Characteristics:

•Loss of epithelial polarity and cell-cell contacts
•Aberrant cell-substrate adhesion
•Degradation of basement membrane
•Increased proliferation and cell migration
•Increased cell invasion
•Occurs during morphogenesis (transient), and tumor
• progression (stable).
Architecture of cell-cell contacts
      Protein Phosphorylation is a key
   mechanism of regulation of cell function

                 Tyrosine kinases

             Serine/threonine kinases

    Phosphatases (eg PTPB1, SHP, PTEN)

Balance between phosphorylation and dephosphorylation
         The WNT/APC pathway




Mutation of APC blocks     _
degradation of -catenin




                           Nat Med. 2004 Aug;10(8):789-99.
   Regulation of -catenin signaling




(Fodde et al., Nature Reviews Cancer 1, 55 –67, 2001)
        Regulation of -catenin function
Normal Epithelial cells:
•APC complexes with GSK and -catenin
•GSK mediates tyrosine phosphorylation of -catenin
•Phosphorylated -catenin becomes susceptible to degradation
by proteosomes.
•Cytoplasmic pool of -catenin is low.

Malignant epithelial cells:
•Wnt/frizzeled pathway is activated
•GSK is inhibited. -catenin remains nonphosphorylated
and is protected from degradation.
•Cytosolic pool of -catenin increaes and -catenin is
translocated to the mucleus to facilitate gene transcription
       (Myc, Waf1, cyclin D1)
Mutations
 in APC
         Summary of APC effect on
            catenin signaling
1. APC facilitates degradation of beta catenin in normal
Cells resulting in decreased nuclear signaling.

2. The selective advantage provided by loss of APC
function resides in the uncontrolled activation of the
WNT/-catenin signal transduction pathway.

3. -catenin acts with LEF1 to activate transcription
of tumor promoting genes such as Myc and Cyclin D1.
ErbB2 IGF1R                  Met
                                        Schlessinger lab.
          Up-regulated in human breast cancer
                                          Nature 411, 355-365 (17 May 2001)
Receptor tyrosine kinase pathways




                  Nature Med. 10:789-99, 2004)
                    Cellular signalling Pathways (1995)
                              Hunter T. Cell. 1995 80:225-36, 1995.




PTEN




 Survival




            Stat3
CELLULAR SIGNALLING NETWORKS (2005)




           Papin et al. Nat Rev Mol Cell Biol.6:99-111, 2005
ErbB receptor family

•There is no known
ligand for ErbB-2
(Her-2/neu).

•ErbB-2 is activated
through transactivation
of heterodimers.

•Over-expression and
activation of erbB-2
correlates with recurrence
and poor survival in
breast cancer patients.

Nature Reviews Cancer 5:342-54, 2005
 ErbB-receptor ectodomain structures

 ErbB2/3 heterodimers are activated
 Through binding of NRG to ErbB3

 Herceptin derivatives bind to ErbB2
 Preventing heterodimerization.

 How do over-expressing ErbB2 cancer
 Cells excape from herceptin?
•Co-ordinate activation of other RTKs
(IGF1R, EGFR, Met)
•Compensatory downstream pathways
Become constitutively activated
(PI3K/Akt-induced survival)
•Loss of suppressor functions (PTEN)
      Nature Reviews Cancer 5:342-54, 2005
c-Src is recruited to adherens junctions
           and focal adhesions

   Adherens junction                     Focal adhesions
                                                    ECM

                                                  


                        Catenins
    Cytoskeletal                          PTPB       FAK
     Proteins                                            Cytoskeletal
                                  PTPB           c-S rc
                   c-S rc                                    Proteins
                            FAK
Src kinase in normal and malignant
        breast development

•Required for normal ductal morphogenesis.

•Shows increased activation in most human breast
carcinomas.

•Required, but not sufficient, in mammary
tumourigenesis in transgenic mice.
Activated Src induces disruption of cadherin junctions

                                          Aggregation



                     c-Src inhibition




      Weak                                    YES
      Yes            Ca++ dependency          No
      Yes               SCATTER               No
       Regulation of cadherin-based
      adherens junctions by Src kinase

1) Activated Src binds to the cadherin complex.

2) Src causes phosphorylation of -catenin, causing its
   dissociation from the cadherin complex and
   endocytosis of the cadherins.

3) Src-induced de-regulation of E-cadherin requires
   integrin signalling.

Frame et al. Nat Rev Cancer 5:505-15, 2005. & Cells Tissues Organs. 179:73-80, 2005.
New concept: Cross talk between growth factor and integrin-
 based cell adhesion signalling is linked to invasive cancer



•Focal adhesion kinase (FAK)
is a substrate of Src.

•Src and FAK link growth factor
 receptors and integrin adhesion
molecules.

•Interaction between growth
factor receptors and integrins
causes increased cell survival
and invasion of carcinomas.

   (Frame et al. Nat Rev Cancer. 5:505-15, 2005.
The metastatic cascade
Nature Reviews Cancer 4, 448-456 (2004
EMT is a reversible process that occurs at distinct
           stages of tumor progression




             (Thiery, Nature Cancer Rev. 2, 442-454, 2002)
Intravasation/extravasation model
        Examples of metastasis genes

             Enhancers                Suppressors
  Tumor cell         Stromal cell      Tumor cell

   HGF/Met           Proteinases      E-cadherin
    Her2/neu        ECM proteins    TIMPs (inhibits
 Akt2 (survival,    (Osteopontin)      proteases)
    invasion)                       Csk (blocks Src)
   N-cadherin                        TGF- (blocks
(cross talks with                    Proliferation)
     RTKs)
             Metastasis issues

1) A 1 cm dia. tumor sheds 2.5 x 106 per day into
blood.
2) Only 0.01% of tumor cells in blood will
metastasize.
3) The majority of tumor cells that arrest in target
organs are dormant or will die.
4) Tumor cells arrest by mechanical restruiction in
target organs: integrin adhesion does not play a role
until after extravasation.
4) BUT, engagement of integrins are required for
outgrowth of metastatic foci (Mercurio)
Tumor Dormancy




Chambers et al. Nature Rev. Cancer 2:563, 2002.
Why are the new wonder drugs having only
minimal effects in treating human cancer?




                  Leaf, C. Fortune 149: 76-82, 84-6, 88 , 2004.
What can we do to improve treatment outcomes?

•Develop preventive measures (life styles, screening for
susceptibility)

•Understand the early stages of cancer and identify early
diagnostic markers.
(gene expression and signalling networks)

•Develop better prognostic indicators (detect the invisible high
risk group).

•Develop better predictive markers (tailor treatments to individual
cancers)
•Develop means of controlling the disease.
       Is it worth while to target tumor dormancy to prevent
metastasis?

				
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