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Cell Biology of Cancer Lingle NCCTG Patient Advocates

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					Cell Biology of Cancer




   Wilma Lingle, PhD
 Experimental Pathology
       Mayo Clinic
Biology of
Breast Cancer
Neoplastic Transformation
 Normal          Cancer
          Basement membrane (basal
                   lamina)
• Basement membrane is an
  extracellular matrix located:
    – around muscle and fat cells
    – under epithelial tissues (skin,
      lining of gut)
    – under endothelial lining of blood
      vessels
• Basement membrane functions
  include:
    – providing mechanical support for
      attached cells,
    – generating signals that maintain
      cell survival,
    – separating adjacent tissues
    – acting as barrier to some
      macromolecules
        Differentiation and cancer




     Tissue
  specificity            Tumor formation
(differentiated         (dedifferentiation)
     state)
Invasion - Metastasis
1. Oncogenes
2. Tumor suppressors
3. Therapeutic targets
4. Cellular and biochemical
mechanisms of chemical or
genetic carcinogenesis
What Is A Tumor Suppressor Gene?

Narrow definition: A gene that encodes a protein that
normally functions to control cell division (Knudson,
1993).

Broader definition: A gene that encodes a protein
that normally functions to suppress the expression of
traits associated with the malignant phenotype.
  Functions of cellular proto-oncogenes
1. Secreted Growth Factors



                             2. Growth Factor Receptors


                                4. Nuclear
                                Proteins:
                              Transcription
      3. Cytoplasmic             Factors
   Signal Transduction
          Proteins
                               Cell Growth
                                 Genes
       Chromosome changes in cancer




Cancer karyotype            Stable karyotype
Tumor Suppressor Genes Encode Proteins
that Suppress the Expression of Traits
Associated With the Malignant Phenotype.

“The malignant phenotype” is a spectrum of traits
commonly associated with tumorigenesis:

   •Increased cellular proliferation.
   •Decreased apoptosis.
   •Increased cellular motility and invasive ability.
   •Decreased contact inhibition.
   •Decreased dependence on growth factors.
How Do Tumor Suppressor Genes Fail?

Tumor suppressor genes function normally to repress the
expression of traits associated with the malignant
phenotype.

Why and how do tumor suppressor genes lose this
repressive function during tumorigenesis?

   Tumor suppressor genes become inactivated
   during tumorigenesis.

   The loss of function of tumor suppressor proteins
   facilitates tumorigenesis.
Interphase               Prophase




             Metaphase   Anaphase
    Cell Cycle Checkpoints
•   Regulate progression through the cell cycle
    insuring that each step takes place only once and
    in the right sequence

•   There are three major checkpoints:
    G1/S (where most cancer-related defects occur)
    G2/M
    Spindle checkpoint
Cancer Evolution
 •   Deregulation Of Cell Cycle

 •   Centrosome Defects

 •   Phenotypic Heterogeneity

 •   Selection Of Aggressive Cancer
     Cells

 •   Molecular Targeted Therapy To
     Delay Chemo-resistance And
     Metastasis
Errors in Mitosis




• Centrosomes   • Kinetochores   • Telomeres
Errors in Mitosis
             No cell is an island




Cells are continuously responding to signals from the
endogenous and exogenous environment.
Signal input dictates disparate cellular outcomes
Biology of Breast Cancer
Proliferative Signaling Pathways
            EGFR

           P*EGFR     Other RTKs

 PI3K      RAS/RAF STAT1/3

 AKT        ERK1/2


P*AKT      P*ERK1/2 P*STAT1/3

  cell         proliferation
survival
The Epidermal Growth Factor Family of
     Tyrosine Kinase Receptors
GF

                    GF                  GF




                                P                   P
EGFRs




        EGFRs




                EGFRs

                        EGFRs




                                    EGFRs

                                            EGFRs
                                P                   P
                                     P       P
  The EGFR Family Members can
form Homodimers or Heterodimers

           GF                 GF                    GF




P                  P   P                 P   P                 P




                                                        EGFR
                                                 EGFR
    HER2

            HER2




                           HER2

                                  EGFR




P                  P   P                 P   P                 P
    P       P               P      P              P      P
        Mechanisms to Inhibit EGFR Activity
GF
         X
                          GF                   GF
MAB




                                       X
                                       P                    X
                                                            P
 HER2




             HER2




                       HER2

                              EGFR




                                           EGFRs

                                                    EGFRs
                                 SMI   X
                                       P                SMI
                                                   X X
                                                   P P
       More than 40% of BC Patients
     Relapse within 5 years of diagnosis

• Inadequate
  surgeries or
  treatment

• Drug resistance

• Evolution of tumor
  cells resistant to
  initial treatment

            How can response to EGFR
             Therapies be monitored?
 Assessing Circulating Tumor Cells to
         Monitor Response

Traditionally, BC patients are followed only by
frequent mammograms and manual breast exams,
making it difficult to monitor response to therapy.


But - invasive cancers shed malignant cells into the
bloodstream. We propose to collect these cells
before treatment and at intervals after treatment in
order to monitor the patient’s response.
   Assessing Circulating Tumor Cells to
    Monitor Response EGFR-Targeted
                Therapies
Our Hypotheses:

  Patients with initial good response will have:
  • a high baseline ratio of P-EGFR to EGFR
  • significant baseline levels of P-AKT and P-ERK1/2
    - indicating that activation of the EGFR pathway
    is involved in the primary tumor.


   Patients with continued good response will have:
   • a lower follow-up ratio of P-EGFR to EGFR
    - indicating inhibited activation of EGFR.
   Assessing Circulating Tumor Cells to
    Monitor Response EGFR-Targeted
                Therapies
Our Hypotheses (cont):

 Patients with continued good response will also have:
 • diminished P-AKT and P-ERK1/2 at follow-up
   - indicating that other activators of proliferation are
      not present.

  Patients with failure to maintain response will have:
  • an increase in P-AKT and P-ERK1/2 in the absence
     of P-EGFR at follow-up
   - indicating that proliferation is being stimulated by
      another receptor tyrosine kinase. These patients
      are no longer benefiting from treatment; their
      treatment should be changed.

				
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