7- Cancer Stem Cells Flashcards
What is the historical overview of CSCs? (4x)
- evidence of tumor heterogeneity
- miscroscopic examination of solid/ liquid tumors
> saw different cell types (looked heterogeneous) - transplantation experiments
> 10^3-10^7 cells needed to efficiently transplant tumor into new host
> suggests not all cells can regenerate/ create a tumor - teratocarcinoma analysis (benign/ derived from ESCs)
> composed of both highly tumorigenic/ well-differentiated (non-tumorigenic) cells - H-thymidine DNA labelling experiments in leukemia patients
> most tumor cells = post-mitotic/ continuously replenished by a small fraction (5%) that cycle rapidly
What did all the heterogeneity evidence suggest about tumors?
- tumors have hierarchical cell organization
What are the levels of the hierarchical cell organization?
self-renewing stem cell
> transit-amplifying/ progenitor cells
> post-mitotic/ differentiated cells
What are the implications of the theoretical CSC? (3x)
- generate a large # of cells from only 1 division
- do not divide constantly, only periodically (quiescent)
- do not represent the majority of proliferative cells in the tumor
What is a major cause of relapse in patients?
- inability to eradicate CSCs
- since therapies target dividing cells/ only divide periodically
What are the 2 models of tumor heterogeneity?
Stochastic Model
- tumors are biologically homogeneous/ functional heterogeneity caused by random influences at a given moment that affect the behaviour of individual cells within the tumor > intrinsic/ extrinsic
Hierarchy Model
- tumors are like normal tissue where cell hierarchies are maintained by stem cells
> heterogeneity caused by CSCs (biologically distinct/ self-renewing)
What is another term for CSC?
TIC = tumor-initiating cell
What are the random influences in the stochastic model?
Intrinsic- degree of cell signalling activation/ levels of TFs
Extrinsic- host factors > microenvironment/ immune response
How is a CSC defined by the hierarchy model?
- ability to self-renew
- able to recapitulate tumor heterogeneity through differentiation
What do the stochastic/ hierarchy model have in common?
- both predict that only a fraction of cells in tumor can initiate tumor growth/ neither predicts frequency of CSCs in a tumor
What are the differences between the stochastic/ hierarchy model?
Stochastic Model
- all cells in tumor are biologically similar in oncogenic capacity
- any cell can become a TIC, given the right influences
> therapy should be designed to target all tumor cells
Hierarchy Model
- CSCs are biologically distinct from majority of cells in tumor
- CSCs responsible for generating other tumor cells
> therapy should be designed to target CSCs
What cancer type were CSCs first discovered in?
AML (acute myeloid leukemia)
What was needed to test the hierarchy/ CSC model? (2x)
- ability to purify subpopulations of tumors based on properties (surface antigen expression)
- functional transplantation assay to test ability of cell populations to generate tumors in vivo
Why were CSCs first identified in AML? (4x)
- accumulated knowledge on hematopoiesis
- well-characterized hematopoietic cell surface antigens
- availability of xenotransplantation assays > SCID mice
- cell-sorting methods > FACS
How can CSCs be identified?
FACS = Fluorescent-activated cell sorting
- fluorescent antibodies label cell surface antigens
- separate populations based on fluorescent intensity
How are CSC/ TICs identified in many different cancers?
- CSC cell surface markers (different)
What are the main CSC cell surface markers for breast cancer?
CD44 high/ CD24 low
What are the 2 possibilities of CSC origin?
- stem cell compartment (of normal tissue) undergoes transforming mutation (already has stem cell characteristics)
- progenitor compartment (of normal tissue) > transforming mutation must be strong enough to induce stem cell features
Are standard therapies targeting CSCs?
- no > why patients relapse
- CSCs evade standard therapies (chemo/ radiation)
- breast CSC population ↑/ higher mammosphere forming efficiency after treatment
Is the CSC fraction defined/ constant within a tumor/ comparable among tumors of same type?
- no > CSC heterogeneity is a problem for treatment
- tumor evolution > ↑ heterogeneity (already to begin with)
> different responses to therapy - CSCs can be generated de novo > EMT (tumor cell plasticity)
What is a source of stem cells?
EMT (epithelial-mesenchymal transition)
- new CSCs can be generated (promotes stem-like properties)
How does tumor cell plasticity further complicate things?
- ↑ plasticity enables bidirectional interconvertibility between CSCs/ non-CSCs (transit-amplifying/ progenitor cells)
- CSCs = moving target
Why do CSCs not respond to conventional therapy? (3x)
- quiescent (divide periodically, not constantly)
- have activated anti-apoptotic programs
- express drug resistance transporters (drug pumps)
What are the 3 main challenges to target CSCs?
- CSCs do not respond to conventional therapies
- Hard to define CSC “unique” signalling pathways since they share many with normal stem cells
- Moving target (replenished due to tumor cell plasticity/ EMT)
What are 2 CSC-targeted therapy approaches?
- Knowledge-based approaches
- Blind approaches (screen to find selective inhibitors of CSCs)
How do we now think of CSCs?
- functionally distinct population that is stochastically renewable
- both models must be accounted for in therapy design
What is the best possible cancer therapy?
- kill proliferating tumor cells + CSCs > remission cure
What is the problem with therapies that kill proliferating tumor cells but not CSCs?
- tumor shrinks > residual CSCs > tumor regenerates
What is a potential problem with therapies that only kill CSCs?
- tumor degenerates BUT rapidly proliferating tumor cells could become new CSCS with new phenotypes
(replenish CSCs even if we get rid of initial population)
