TUMOR INITIATING CELLS: THE STEM CELL THEORY OF CANCER

Transcription

1 Pr John DE VOS Département d Ingénierie Cellulaire et Tissulaire INSERM IRMB Hôpital St Eloi - CHU de Montpellier TUMOR INITIATING CELLS: THE STEM CELL THEORY OF CANCER

2 Plan o Stem cells o The stem cell theory of cancer : tumor initiating cells o The leukemia model o Identifying cancer stem cells (CSC)? o Limits of the model

3 STEM CELLS

4 Hierarchical organization of tissues o Tissues are composed of a heterogeneous array of cells, with a hierarchical organization : o during development o in a given tissue o There are differences : o in the degree of specialization o the capacity of proliferation o the capacity of self-renewal o Concept first development in hematology

5 Hierarchical organization of tissues Stem cell Precursor/progenitor («transit amplifying cells») Differentiated cells

6 Stem cells o Essential features: o Undifferentiated cells o Self-renewal o Differentiation o Functional definition, a hidden property that must be demonstrated by functional tests Stem Cell Progenitor Differentiated cell

7 Classification of stem cells o origin : o embryonic, o foetal o adult o differentiation capacity o Unipotent SC o Multipotent SC o Pluripotent SC

8 Differentiation of stem cells o Divisions: o asymetric o stochastic model Divisions asymétriques Modèle stochastique

9 The stem cell niche o Microenvironment maintains the stem cell property o A way to regulate stem cell numbers Symetric division Asymetric division

10 CANCER STEM CELLS

11 Is a tumor homogeneous? o Within a malignant tumor or among the circulating cancerous cells of a leukemia, there can be a variety of types of cells : phenotypic heterogeneity (beware : different from genetic heterogeneity) o The stem cell theory of cancer proposes that among all cancerous cells, a few act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells normally renew and sustain our organs and tissues

12 Cancer Stem Cells (CSC) o Definition: o theory : a cell with self renewal capacity, capable to produce a new tumor; theoretically, a single CSC could give rise to a new tumor. o Origin of CSC : only the SC live enough to accumulate the DNA modifications necessary for the malignancy to arise o consequences : Functional test : a CSC will produce a tumor in an immunosuppressed mice; or can be genetically traced in mice cancer models May display some markers of normal SC Major potential clinical consequences

13 THE LEUKEMIA MODEL

14 THE LEUKEMIA MODEL

15 The leukemia model o Normal hematopoietic stem cells : CD34+ CD38- o And in leukemia?

16 The leukemia model o Graft into the immunosuppressed mice NOD/SCID

17 The leukemia model o Graft into the immunosuppressed mice NOD/SCID

18 The leukemia model

19 The leukemia model

20

21 Sugihara et al. Int J Can 2013

22 IMPLICATIONS FOR TREATMENT

23 Implication for cancer therapies o If the concept of the CSC is true: o It would explain the heterogeneity of tumors o It would have wide implications for cancer therapies! o Only anti-cancer treatments killing CSC would prevent relapse o Industry : anti-csc programs

24

25 Nature Sep 17;525(7569):380-3

26 Targeting self-renewal, an Achilles' heel of cancer stem cells M. S. Wicha, Targeting self-renewal, an Achilles' heel of cancer stem cells., Nat Med, vol. 20, no. 1, pp , Jan

27 Cancer treatment by differentiation o Acute myeloblastic leukemia (AML3) o PML/RAR translocation : retinoic acid receptor o Treatment with all-trans retinoic acid (ATRA) o Poor prognostic è Good prognostic o AML and CD44

28 Traitement par différenciation Nat Med, vol. 5, no. 6, pp , Jun

29 IDENTIFYING CSC

30 IDENTIFYING AND ISOLATING CSC Sugihara et al. Int J Can 2013

31 CSC MARKERS

32 Side population : SP o Hoechst 33342: o cell-permeable DNA stain excited by ultraviolet light and emits blue fluorescence at nm o Binds to DNA o Actively transported out of the cell via ABC transporters o Negative population SP is enriched in SC

33 ALDH ACTIVITY o Aldehyde dehydrogenases : group of enzymes for detoxification of exogenously and endogenously generated aldehydes o ALDH+ cells are enriched in SC [1] C. Ginestier, M. H. Hur, E. Charafe-Jauffret, F. Monville, J. Dutcher, M. Brown, J. Jacquemier, P. Viens, C. G. Kleer, S. Liu, A. Schott, D. Hayes, D. Birnbaum, M. S. Wicha, and G. Dontu, ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome., Stem Cell, vol. 1, no. 5, pp , Nov

34 Spheroids o Floating cell aggregates o Phenotypic heterogeneity o Long term growth (with passages) : only if CSC

35 FUNCTIONAL TESTS

36 LIMITS

37 ARE CSC RARE?

38 ARE CSC RARE?

39

40 ARE CSC RARE? o CSC melanoma : o 1/ (Nature Jan 17;451(7176):345-9) o 1/4 (Nature Dec 4;456(7222):593-8) o Depends of the functional test!!! o è Concept of tumor initiating cells (TICs)

41 TARGETING CSC BUT NOT SC o If CSC have a similar metabolism to SC, treating CSC may target normal SC

42 OTHER MODELS

43 OTHER MODELS? Sugihara et al. Int J Can 2013

44 CLONAL EVOLUTION OF AML L. Ding, T. et al, Clonal evolution in relapsed acute myeloid leukaemia revealed by wholegenome sequencing., Nature, vol. 481, no. 7382, pp , Jan

45 Differentiation reversibility Sugihara et al. Int J Can 2013

46 EMT? Sugihara et al. Int J Can 2013

47 Niche indepedency Batlle, E., & Clevers, H. (2017). Cancer stem cells revisited. Nat Med, 23(10),

48 OTHER (NOT EXCLUSIVE) o Differentiation blockage o Reproduction of fetal or embryonic properties o New phenotype

49 CTC!

50 Circulating tumor cells o Circulating tumor cells = CTC Science, 2013, 341(6151),

51 CONCLUSION o High stakes o Difficult to formally prove the CSC theory o New pathways of research: o Genetic tracing (mouse models) o Single cell mrnaseq and DNAseq

52 Bibliography o Three recent reviews: o Batlle, E., & Clevers, H. (2017). Cancer stem cells revisited. Nat Med, 23(10), o Nassar, D., & Blanpain, C. (2016). Cancer Stem Cells: Basic Concepts and Therapeutic Implications. Annu Rev Pathol, 11, o (2017). Looking Back: Cancer Stem Cells. Cell Stem Cell, 20(6), 754.