Stem Cells & Cancer
description
Transcript of Stem Cells & Cancer
![Page 1: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/1.jpg)
Stem Cells & Cancer
Norman Iscove M.D.
![Page 2: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/2.jpg)
Multiple kinds of blood cell
![Page 3: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/3.jpg)
Bone marrow is a factory for blood cells
![Page 4: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/4.jpg)
Multiple assembly lines in marrow
![Page 5: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/5.jpg)
The neutrophil assembly line
![Page 6: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/6.jpg)
The neutrophil assembly line
![Page 7: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/7.jpg)
The neutrophil assembly line
![Page 8: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/8.jpg)
The neutrophil assembly line
![Page 9: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/9.jpg)
The neutrophil assembly line
![Page 10: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/10.jpg)
The neutrophil assembly line
![Page 11: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/11.jpg)
The neutrophil assembly line
![Page 12: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/12.jpg)
The neutrophil assembly line
![Page 13: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/13.jpg)
The neutrophil assembly line
![Page 14: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/14.jpg)
The neutrophil assembly line
![Page 15: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/15.jpg)
The neutrophil assembly line
![Page 16: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/16.jpg)
The neutrophil assembly line
![Page 17: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/17.jpg)
The neutrophil assembly line
![Page 18: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/18.jpg)
Multiple assembly lines
![Page 19: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/19.jpg)
Where do precursor cells come from?
![Page 20: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/20.jpg)
Stem cells self-renew
Stem cell
Committed precursors
Differentiating precursors
![Page 21: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/21.jpg)
Stem cells self-renew
Stem cell
![Page 22: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/22.jpg)
Stem cells self-renew
Stem cell
![Page 23: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/23.jpg)
Committed precursor
Stem cells self-renew
Stem cell
![Page 24: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/24.jpg)
Committed precursor
Differentiating precursor
Stem cells self-renew
Stem cell
![Page 25: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/25.jpg)
Stem cells self-renew
Stem cell
Committed precursors
Differentiating precursors
![Page 26: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/26.jpg)
Stem cells self-renew
Stem cell
![Page 27: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/27.jpg)
Stem cells self-renew
Stem cell
![Page 28: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/28.jpg)
Committed precursor
Stem cells self-renew
Stem cell
![Page 29: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/29.jpg)
Committed precursor
Differentiating precursor
Stem cells self-renew
Stem cell
![Page 30: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/30.jpg)
Stem cells self-renew
Stem cell
Committed precursors
Differentiating precursors
![Page 31: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/31.jpg)
Stem cells self-renew
Stem cell
![Page 32: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/32.jpg)
Stem cells self-renew
Stem cell
![Page 33: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/33.jpg)
Committed precursor
Stem cells self-renew
Stem cell
![Page 34: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/34.jpg)
Committed precursor
Differentiating precursor
Stem cells self-renew
Stem cell
![Page 35: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/35.jpg)
Cao et al., PNAS 101:221-226, 2004
Marrow cells
FACS
Stem cells
Remaining cells
Stem cellsOther precursors
Stem cells are the key transplantable element in marrow
time1 stem cell
1 in 20,0001 in 4,000
Stem cells can be purified
Imaging of stem cell transplantation
![Page 36: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/36.jpg)
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
![Page 37: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/37.jpg)
Differing biology of precursor cells and stem cells
proliferative
![Page 38: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/38.jpg)
Differing biology of precursor cells and stem cells
killed by anti-cancer drugs
![Page 39: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/39.jpg)
Differing biology of precursor cells and stem cells
quiescent
![Page 40: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/40.jpg)
Differing biology of precursor cells and stem cells
relatively resistant to anti-cancer drugs
![Page 41: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/41.jpg)
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
![Page 42: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/42.jpg)
Stem cells in normal mammary glands
Stingl et al, Nature 439:993, 2006
1 in 1500 mammary ductal cells can regenerate an entire gland
1 purified cell is sufficient
![Page 43: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/43.jpg)
Leukemia
Leukemia
Normal
![Page 44: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/44.jpg)
Leukemia initiating cells are rare and distinct
time
humanleukemiacells
florid leukemia
1 in 50,000 cells
1 %
leukemia cells
FACS
Stem cells
Remaining cells99 %
Dick et al, 1997
![Page 45: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/45.jpg)
Breast tumour initiating cells are rare and distinct
time
Breast carcinoma
1 %
breast tumour cells
FACS
Stem cells
Remaining cells99 %
Clarke et al, 2003
Human breast carcinoma cells
![Page 46: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/46.jpg)
Brain tumour initiating cells are rare and distinct
time
Brain tumour
1 %
brain tumour cells
FACS
Stem cells
Remaining cells99 %
Dirks et al, 2004
Human brain tumour cells
![Page 47: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/47.jpg)
Colon tumour initiating cells are rare and distinct
time
Colon carcinoma
1 %
colon carcinoma cells
FACS
Stem cells
Remaining cells99 %
Dick et al, 2006
Human colon carcinoma cells
![Page 48: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/48.jpg)
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
![Page 49: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/49.jpg)
Differing biology of precursor cells and stem cells
killed by anti-cancer drugs
relatively resistant to anti-cancer drugs
![Page 50: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/50.jpg)
relapseremission
Jean Wang
early cure
eventual cure
Tumour stem cell
Stem cell concepts will change treatment strategies
treatment
conventional bulk reduction
stem cell targetted
combined anti-stem and bulk reduction
![Page 51: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/51.jpg)
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
![Page 52: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/52.jpg)
![Page 53: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/53.jpg)
In leukemia, clinical illness requires interference with differentiation, mutational load may be complex
In solid tumours, clinical change only requires local growth
![Page 54: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/54.jpg)
STOCHASTICMODEL
HIERARCHYMODEL
NO TUMOR
NO TUMOR
NO TUMOR
NO TUMOR
NO TUMOR
NO TUMOR
Models of tumor heterogeneity
Jean Wang
![Page 55: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/55.jpg)
CD133+BRAINCANCER
Injectioninto brain 2004
AMLCD34+CD38
Intravenousinjection 1997
CD44+CD24
Injection into mammary fat pad 2003
BREASTCANCER
CD44+
HEAD & NECKCANCER
Subcutaneousinjection 2007
Identification of cancer-initiating cells
CD133+
Injection under renal capsule 2007
COLONCANCER
or subcutaneousinjection
Jean Wang
![Page 56: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/56.jpg)
ResidualC-ICs
Tumor regeneratesRELAPSE
Tumor shrinksTHERAPIES THATKILL PROLIFERATING
TUMOR CELLS BUT NOT C-ICs
THERAPIES THATKILL C-ICs
Tumor degeneratesCURE
Development of effective anti-cancer therapies
REMISSION
THERAPIES THATKILL PROLIFERATING
TUMOR CELLS AND C-ICs
CURE
REMISSION
Jean Wang
![Page 57: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/57.jpg)
The neutrophil assembly line
![Page 58: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/58.jpg)
The neutrophil assembly line
![Page 59: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/59.jpg)
The neutrophil assembly line
![Page 60: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/60.jpg)
0 110 110
0 204 153
128 0 128
0 0 2550 216 159
0 194 143
128 128 128
128 0 0
Test
Test2
RholoLy6Ahic-kit+B220-CD3-
1 x 106
![Page 61: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/61.jpg)
9 Gy
BM
BMtime
RKSL
CD49b- CD49b+
KL/FL/7/11
Onset of cell division
![Page 62: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/62.jpg)
LTRC orSTRC 24 hr
1 x 106
9 d
100 cells KL/FL/7/11
![Page 63: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/63.jpg)
Stem Cells
• persist throughout adult life
• responsible for permanence of cell-turnover systems
• generate differentiating progeny
• generate undifferentiated progenythat remain primitive
![Page 64: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/64.jpg)
0.0
0.2
0.4
0.6
0.8
1.0
00 20 40 60 80
![Page 65: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/65.jpg)
1
10
100
5 10 150
days360
1
10
100
![Page 66: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/66.jpg)
![Page 67: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/67.jpg)
![Page 68: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/68.jpg)
Leukemia
![Page 69: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/69.jpg)
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
![Page 70: Stem Cells & Cancer](https://reader036.fdocuments.us/reader036/viewer/2022062322/56814404550346895db096b9/html5/thumbnails/70.jpg)
950 rBM cells
Short term "CFC" assays