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Stem Cells _ Cancer.ppt

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					Stem Cells & Cancer


Norman Iscove M.D.
Multiple kinds of blood cell
Bone marrow is a factory for blood cells
Multiple assembly lines in marrow
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
Multiple assembly lines
Where do precursor cells come from?
 Stem cells self-renew

Stem cell




Committed
precursors


Differentiating
precursors
Stem cells self-renew

Stem cell
Stem cells self-renew

Stem cell
 Stem cells self-renew

Stem cell




Committed
precursor
 Stem cells self-renew

Stem cell




Committed
precursor


Differentiating
precursor
 Stem cells self-renew

Stem cell




Committed
precursors


Differentiating
precursors
Stem cells self-renew

Stem cell
Stem cells self-renew

Stem cell
 Stem cells self-renew

Stem cell




Committed
precursor
 Stem cells self-renew

Stem cell




Committed
precursor


Differentiating
precursor
 Stem cells self-renew

Stem cell




Committed
precursors


Differentiating
precursors
Stem cells self-renew

Stem cell
Stem cells self-renew

Stem cell
 Stem cells self-renew

Stem cell




Committed
precursor
 Stem cells self-renew

Stem cell




Committed
precursor


Differentiating
precursor
Stem cells are the key transplantable
element in marrow
   Stem cells can be            Imaging of stem cell
   purified                     transplantation
         Marrow cells           1 stem cell                time



             FACS




Stem cells
                               Other precursors             Stem cells
             Remaining cells      1 in 4,000                1 in 20,000

                                                  Cao et al., PNAS 101:221-226, 2004
Normal blood cell formation

   • blood cells produced by maturation of precursor cells
   • precursor cells have finite proliferative capacity and
       lifespan

   • stem cells are multipotent
   • stem cells constantly replenish the precursor cells
   • stem cells make new stem cells - "self-renewal"
   • self-renewal is unique to stem cells and is essential
       for continued existence of blood cell production
Differing biology of precursor cells and
stem cells




   proliferative
Differing biology of precursor cells and
stem cells




   killed by anti-
   cancer drugs
Differing biology of precursor cells and
stem cells

   quiescent
Differing biology of precursor cells and
stem cells

   relatively resistant
   to anti-cancer
   drugs
Differing biology of precursor cells and
stem cells


   • >95% of marrow cells can be depleted by treatment
       with certain anti-cancer drugs
   • stem cells may entirely resist short-term chemotherapy

            Despite massive reduction in marrow bulk by
            chemotherapeutic agents, marrow will rapidly
            regenerate from surviving stem cells
Stem cells in normal mammary glands




                 1 in 1500 mammary ductal cells
                 can regenerate an entire gland

                 1 purified cell is sufficient

                          Stingl et al, Nature 439:993, 2006
Leukemia


Leukemia




  Normal
Leukemia initiating cells are rare and distinct

              human                                  leukemia cells
              leukemia
              cells

 1 in 50,000 cells
                                                         FACS


                     time



                                        Stem cells
                                           1%
                                                          Remaining cells
                      florid leukemia                         99 %


                                               Dick et al, 1997
Breast tumour initiating cells are rare and
distinct
                 Human breast
                 carcinoma cells             breast tumour cells




                                                    FACS


          time



                                    Stem cells
                                       1%
                                                      Remaining cells
                 Breast carcinoma                         99 %


                                           Clarke et al, 2003
Brain tumour initiating cells are rare and
distinct
                      Human brain
                      tumour cells
                                              brain tumour cells




                                                     FACS


          time



                                     Stem cells
                                        1%
                                                       Remaining cells
                 Brain tumour                              99 %


                                            Dirks et al, 2004
Colon tumour initiating cells are rare and
distinct
                Human colon
                carcinoma cells            colon carcinoma cells




                                                  FACS


         time



                                  Stem cells
                                     1%
                                                    Remaining cells
                Colon carcinoma                         99 %


                                         Dick et al, 2006
Cancer stem cells

    • cancers, like normal tissues, constitute differentiating
        systems
    • bulk cells produced by cancer systems have
        abnormal properties       clinical disease
    • bulk cells have finite lifespans

    • cancer stem cells are rare and physically distinct
        from the bulk of tumour cells
    • cancer stem cells are essential to the continued
        existence of cancer systems
    • the biology of cancer stem cells differs from the rest
        of the cells in a tumour
Differing biology of precursor cells and
stem cells

   relatively resistant
   to anti-cancer
   drugs


   killed by anti-
   cancer drugs
Stem cell concepts will change treatment
strategies
 treatment                 remission     relapse

 conventional
 bulk reduction


 stem cell                               eventual
 targetted                               cure

 combined anti-              early
 stem and bulk               cure
 reduction

                  Tumour stem cell

                                       Jean Wang
Cancer stem cells - future work

    • new advances will be fuelled by the ability to detect
        cancer stem cells specifically

    • new drugs will be identified by their ability to destroy
        tumour forming cells rather than bulk tumour cells

    • stem cell-based treatment strategies will aim for cure
In leukemia, clinical illness requires interference
with differentiation, mutational load may be
complex

In solid tumours, clinical change only requires
local growth
  Models of tumor heterogeneity


STOCHASTIC
  MODEL




                                         NO TUMOR
                      NO TUMOR


HIERARCHY                                NO TUMOR
  MODEL               NO TUMOR
                                         NO TUMOR
                      NO TUMOR
                                  Jean Wang
Identification of cancer-initiating cells
                                 Injection
                                 into brain                  2004
          BRAIN        CD133+
         CANCER
                                Subcutaneous
        HEAD & NECK               injection                  2007
          CANCER
                        CD44+

          BREAST
          CANCER              Injection into
                             mammary fat pad                 2003
           COLON      CD44+CD24
           CANCER
                             Injection under
                              renal capsule                  2007
                             or subcutaneous
                       CD133+ injection


             AML                   Intravenous
                                     injection               1997
                      CD34+CD38


                                                 Jean Wang
    Development of effective anti-cancer therapies
                                       REMISSION                RELAPSE
     THERAPIES THAT         Tumor shrinks     Tumor regenerates
   KILL PROLIFERATING
TUMOR CELLS BUT NOT C-ICs             Residual
                                       C-ICs



     THERAPIES THAT                              Tumor degenerates
                                                                     CURE
       KILL C-ICs



                                      REMISSION
    THERAPIES THAT
  KILL PROLIFERATING                   CURE
 TUMOR CELLS AND C-ICs



                                                              Jean Wang
The neutrophil assembly line
The neutrophil assembly line
The neutrophil assembly line
0 110 110         128 0 0
128 0 128         0 194 143
0 216 159         0 0 255
128 128 128       0 204 153

Test          RholoLy6Ahic-kit+B220-CD3-

Test2                         1 x 106
     9 Gy                                RKSL

BM                                CD49b-     CD49b+
            time
                   BMKL/FL/7/11



                                  Onset of cell division
                                 1 x 106
 LTRC
 or
 STRC                    24 hr       9d
            KL/FL/7/11
100 cells
Stem Cells


  • persist throughout adult life
  • responsible for permanence of cell-
     turnover systems
  • generate differentiating progeny
  • generate undifferentiated progeny
    that remain primitive
1.0


0.8


0.6


0.4


0.2


0.0

      0   20   40   60   80
100
      100


10
      10


  1
        1



            0   5   10    15    360
                         days
Leukemia
A new era in cancer stem cells

               • novel bioassays
               • growth factors / morphogens
               • surface markers
Human acute myeloid leukemia is organized as a hierarchy that originates from a
primitive hematopoietic cell.
Bonnet D, Dick JE. Nat Med. 3:730-7, 1997

Prospective identification of tumorigenic breast cancer cells.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Proc Natl Acad Sci USA.
100:3547-9, 2003

Identification of human brain tumour initiating cells.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD,
Dirks PB. Nature. 432:396-401, 2004
Short term "CFC" assays

                950 r
 BM cells

				
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