1. Cancer stem cell
Hong Shin Deock
종양유전학 발표

2. Contents - Origin of Cancer Stem Cell - Cancer Stem Cell models
- Plasticity in the CSC model
- CSC model-based strategies for cancer therapy
종양유전학 발표

3. Origin of Cancer Stem Cell

4. Origin of Cancer Stem Cell

5. Origin of Cancer Stem Cell

6. Origin of Cancer Stem Cell

7. Origin of Cancer Stem Cell

8. Cancer Stem Cell models

9. Cancer Stem Cell models

10. Plasticity in the CSC model

11. Plasticity in the CSC model
- LT-TIC : Long term Tumor initiating cell
- T-TAC : Tumor transient amplifying cell

12. Different cells of origin result in distinct phenotypes for stem cells
- Ara-C (Cytarabine) : interfere with the synthesis of DNA
- Nutlin-3 : Mdm2 inhibitor

13. Generation of iCSCs

14. CSC model-based strategies for cancer therapy

15. CSC model-based strategies for cancer therapy
- OGC : Other gloima cell
- CSC : Cancer stem cell
- TBV : tumor vasculature

16. Regulation of FOXO transcription factor by PI3K-Akt pathway

17. BCR-ABL

18. Figure 1. Maintenance of CML LICs depends on Foxo3a.
- KLS+ : c-Kit+Lin-Sca-1+
- KLS- : c-Kit+Lin-Sca-1-
- K-LS+ : c-Kit-Lin-Sca-1+
- K-LS- : c-Kit-Lin-Sca-1-
- c-kit(CD117) : Stem cell growth receptor
- Sca-1 : haematopoietic stem cell antigen
- Lin : Lineage from HSCs
- KLS+ : LICs
- KLS- : non-LICs
- CML : Chronic myeloid leukaemia
- LIC : leukaemia initiating cells (CSCs)

19. Figure 1. Maintenance of CML LICs depends on Foxo3a.
- KLS+ (BCR-ABL GFP-)
-> normal haematopoietic stem cell(nHSC)

20. Figure 1. Maintenance of CML LICs depends on Foxo3a.
- WBC : White blood cell
- BMT : Bone marrow transplantation
○ : Foxo3a+/+
■ : Foxo3a-/-
- Foxo3 deficiency prevented the
Propagation of CML cells in the spleen
and peripheral blood
- Foxo3a-/- LICs may retain sufficient
function to cause disease in 2nd BMT,
but not in 3rd BMT

21. Figure 2. Essential role of Foxo3a in suppression of LIC apoptosis
Bone marrow
Spleen
- Tunel assay (red) : detecting DNA fragment
- annexin-V : apoptosis marker
Foxo3a is required for LIC survival

22. Figure 3. TGF-b-Foxo signalling is required for the colony-forming capacity of LICs
- Ly : TGF-b inhibitor
- Imatinib : Tyrosine kinase inhibitor(TKI)
Inhibiton of Foxo or TGF-b may be a Useful to TKI therapy

23. Figure 4. Inhibition of TGF-b-Foxo signalling in combination with TKI therapy depletes CML in vivo
- Imatinib : Tyrosine kinase inhibitor(TKI)
- Ly : TGF-b inhibitor
TGF-b is a critical regulator of Akt and Foxo in LILCs

24. Summary
- Foxo3a has opposite effects on the survival of LICs and non-LICs
- In non-LICs, BCR-ABL drives Akt activation that represses Foxo3a functions
- When block BCR-ABL, activation of Foxo3a leads to apoptosis and cell cycle arrest
- In CML LICs, Akt activity is suppressed despite BCR-ABL expression
- LICs have properties that allow them to resist various stress in a Foxo-dependent manner

25. Summary

26. Reference
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