Cancer stem cells Flashcards
What are the two key observations for tumor growth (cancer stem cell concept)?
- Cancer is composed of heterogeneous cells
2. Only a fraction of cancer cells can propagate tumor
What is the difference between a stochastic model and a hierarchical stem cell model?
Stochastic model: every progenitor cell is capable of forming a cell mass
Hierarchical model: only a fraction of progenitor cells are able to form a cell mass (tumor growth model)
What is the fuel of cancer growth (cancer stem cells)?
Cancer growth is fueled by limited numbers of dedicated stem cells that are capable of self-renewal and hierarchical differentiation to generate mature non-self-renewing cancer cells that constitute the bulk tumor
What are the 3 required properties of a cancer stem cell model?
- Self-renewal confined to distinct cells
- Phenotypic and functional heterogeneity
- Hierarchical organisation
When testing if cancer stem cells truly follow a hierarchical model, what is the difference between potential VS fate?
• Potential: what a cell can do in the conditions tested
– in vitro assays
– transplantation assays
• Fate: what a cell actually does under physiological conditions
– fate-mapping (only possible in hierarchical model)
• Potential ≠ Fate
How does fate mapping cancer stem cells work and what does it show?
Genetic mark introduced into cells to follow if one of the progenitor cells will be clonally dominant (self-renewing stem cells) or not (non-self-renewing cells)
What are the conclusions made about cancer stem cells (CSC)?
- The CSC concept is VALID and has been modeled in mice
- The CSC model is supported in several human cancers but NOT conclusively established
- Experimental approaches, including in vitro culture and xeno-transplantation into mice, does NOT necessarily reveal or exclude cancer stem cell properties
- Some cancers does NOT appear to follow CSC model
What is genetic heterogeneity and why is it important for cancer cells?
It is that multiple genetic hits are required (like driver mutations) for cancer cells development => they gain genetic heterogeneity
This can predispose patients to having cancer
What can be said about pre-malignant states in the population?
Pre-malignant state is COMMON in the general population
Driver mutations can be traced in virtually every individual
What can be said on errors in the genome throughout life?
Continuous accumulation of errors in the genome persist for the life-time of each cells:
- mutations in short-lived cells likely to be lost
- mutations in stem cells will persist
What can be said about cell of origin in cancer stem cells?
Cell-of-origin can directly or indirectly influence the phenotype of cancer cells
Why should we care about cancer stem cells (CSC)?
- Current cancer therapies fail to achieve a cure
- Relapse associated with worse prognosis
- CSCs can selectively escape therapeutic targeting
- CSCs represent cellular origin of relapse
- Elimination of CSCs is required and potentially sufficient to achieve a cure
How are cancer stem cells (CSC) resistant to treatment?
• Quiescence (slow growth) (most therapies target fast dividing cells)
• High levels of anti-apoptotic molecules
• Resistance to DNA or oxidative damage in combination
with efficient DNA repair
• Protected by CSC niche (surrounding stromal cells)
• Low expression of immune-stimulatory molecules
• Clonal selection of tumors that are resistant to treatment (genetic or epigenetic changes)
• Treatment induce mutations promoting resistance
What are the 3 consequences of cancer stem cell (CSC) therapy resistance?
- Contribution to relapse
- Contribution to metastasis
- Lack of available treatment options
Relapse and metastasis is the most common cause of death in cancer
Elimination of CSCs is required but challenging
Need for a better biological understanding of CSCs to promote targeted therapies
Why do we need to eliminate cancer stem cells (CSC)?
• CSCs originate from one single cell
• Cure depend on complete elimination of ALL
cells (challenging)
