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Biology of Cancer > Cancer Stem Cells > Flashcards

Cancer Stem Cells Flashcards

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1
Q

What is a stem cell?

A

A cell that is capable of both self replication and differentiation into other kinds of specialised, functional cells

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2
Q

What is cell differentiation?

A
  • process by which a less specialised cell becomes a more specialised cell type
  • this is through a stable, complex change in gene expression
  • occurs in steps
  • at each step, an immature cell type (precursor/progenitor) changes into a more mature one
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3
Q

What are the 3 types of renewal a stem cell can undergo?

A
  1. Self renewal = divides into 2 identical cells of the same type as the original cell
  2. Differentiation = division into 2 identical cells which are more mature than the original cell type
  3. Asymmetric cell division (ACD) = division into 2 cells which are different to each other - one may be identical to the original cell, the other more mature
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4
Q

What is a committed progenitor cell?

A

Descendants of stem cells which can be further differentiated themselves to produce more specialised cells

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5
Q

What are the different cell stages of stem cells through differentiation?

A
  • Long term stem cell (LT-SC)
  • short term stem cell (ST-SC)
  • early progenitor
  • late progenitor
  • differentiating cells
  • differentiated cells
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6
Q

Which type of stem cells can self renew?

A

long term and short term stem cells can self renewal before they are differentiated into progenitors

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7
Q

Which type of stem cells have the best probability of differentiating?

A
  • Long term and short term stem cells and early progenitors have the best probability
  • after that, probability decreases the more differentiation occurs
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8
Q

What is a cancer stem cell (CSC)?

A
  • a rare immortal cell within a tumour that can both self renew and give rise to many cell types through differentiation
  • these differentiated cells can constitute to the tumour therefore tumours are formed
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9
Q

Why are there cancer stem cells?

A
  • not all the cells within the tumour are equally capable of regenerating the tumour
  • CSCs are the only cells within the tumour with the capacity to maintain and regenerate the rumour as well as being responsible for relapse
  • tumours are therefore stem cell maintained tissues like many other tissues
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10
Q

Should there be CSC-specific therapies?

A
  • Current anti cancer treatments target reduction of tumour mass by targeting non self renewal cells
  • this could eradicate all the non self renewing cells however any CSCs could be resistant and therefore can multiply themselves to relapse a tumour
  • therefore CSC-specific therapy should be used to compliment other therapies to aim to reduce all types of cancer cells
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11
Q

How were CSCs discovered?

A
  • In 1994 , Dick et al. provided evidence of this hypothesis
  • they used cell surface protein markers to identify a rare population of stem-like cells in acute myeloid leukaemia (AML)
  • the cells were present in the peripheral blood of people with AML at approx 1:250,000 cells
  • stem cell-like populations have since been thought to use cell-surface protein makers in breast, colon, pancreas and other cancers
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12
Q

What are properties shared by normal stem cells and CSCs?

A
  1. Self renewal = tissue specific cells must self renew to maintain specific organs, CSCs do the same to maintain tumour growth
  2. Differentiation = normal SCs do this to give rise to a heterogeneous population and there is evidence to show CSCs do the same
  3. Asymmetric cell division = all stem cells are capable of symmetric/asymmetric cell division
  4. Cellular signalling = both have pathways that regulate self renewal
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13
Q

What are some signalling pathways related to CSCs?

A

many CSC subsets and normal tissue SCs share core regulatory genes and development pathways such as:
- hedgehog (Hh)
- Notch
- Wnt
- b-catenin
- NF-kB
- c-MYC
- BMI-1

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14
Q

How does epithelial-mesenchymal transition (EMT) aid CSCs?

A
  • epithelial cells are more proliferative whereas mesenchymal cells are more migratory
  • together they form EMT which enhances CSCs stemless
  • this association has been observed in pancreatic, prostate, colorectal and breast cancer
  • breast cancer cells with high CD44+/CD24- cell number show high stem/progenitor properties and exhibit stro Ng enhanced mesenchymal markers
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15
Q

Do CSCs have selective growth advantage in a non hierarchical model?

A
  • a cell can acquire a series of mutations and produce a dominant clone
  • tumour cells arising from this clone have similar tumourigenic capacity
  • however, other derivatives may lack tumourigenecity
  • therefore tumour heterogeneity results from the diversity of cells present within the tumour
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16
Q

What is tumour cell heterogeneity like in a hierarchical model?-

A
  • a small subset of cells has the ability to sustain tumourigenesis and generate heterogeneity through differentiation
  • a mutation in a progenitor cell endows the tumour with stem cell like properties
  • these cells have self renewing capability and give rise to a range of tumour cells thereby accosting for tumour heterogeneity
17
Q

What is tumour heterogeneity?

A

The observation that different tumour cells can show distinct morphological and phenotypic profiles

18
Q

Where have CSCs been observed in humans?

A
  • 3 studies (2012) identified specific cell subsets that acted as CSCs in the brain, skin and intestinal tumours
18
Q

Where have CSCs been observed in humans?

A
  • 3 studies (2012) identified specific cell subsets that acted as CSCs in the brain, skin and intestinal tumours
18
Q

Where have CSCs been observed in humans?

A
  • 3 studies (2012) identified specific cell subsets that acted as CSCs in brain, skin and intestinal tumours
  • the reports indicated that targeting these specific cells may improve therapeutic outcome
19
Q

Where have CSCs been observed in vivo?

A
  • Parada et al. (2012) showed in a glioma mouse model that tumour cells genetically labelled with Nestin-GF (adult SC marker) have properties consistent with CSCs
  • these cells were able to reinitiate tumour growth following chemotherapeutic inhibition of proliferation
  • specific elimination of the CSCs significantly impaired tumour growth
20
Q

How do CSCs arise through self renewal?

A
  • normal stem/progenitor/differentiated cells can all self renew to form an identical stem cell
  • however this stem cell could undergo gene mutation which would result in the cell now producing both normal stem cells and mutated stem cells.
  • The mutation could cause the self renewal gene to be permanently turned on which would result in rapid cell growth of CSCs
21
Q

Which cancers arise from different stem cells?

A
  • Stem cells = AML originates from a hierarchy of leukaemic stem cell classes that differ in self renewal capacity
  • Progenitor cells = a double maker approach showed that CSCs from gliomas were oligodendrocyte precursor cells
  • Differentiatied cells = therapy-induced developmental reprogramming of prostate cancer has an acquired therapy resistance
22
Q

What happens to the niche when CSCs develop?

A
  • normal niche contains a stem cell, a progenitor cell and supporting cells
  • genetic or epigenetic changes in a stem cell leads to the production of a CSC and therefore an expansion of cells in the niche
  • the niche adapts to the presence of CDCs with its cells changing their properties and the recruitment of cells that would not normally be present
23
Q

How do CSC assays work?

A
  • limiting-dilution transplants or other clonal tracking strategies are used to determine the frequency of CSCs in the initial tumour-derived cell suspension
  • ideally, the tumours that form in primary hosts are tested again for the content of their cells with CSC activity to confirm that the initial CSCs had self replicating abilities
  • the most sensitive assays are those in which there is no immunological difference between the host and the tumour
  • when this is not possible (eg human tumours), xenografts into highly immunodeficient mice are used
24
Q

What evidence is there to show the existence of multiple CSC pool within individual tumours?

A

Cancers can harbour heterogenous and biologically distinct populations of CSCs:
- distinct leukaemic stem cell populations defined by CD34, CD38 and IL3Ra expression
- heterogeneous CSC compartments have been described in solid tumours (ovarian/breast) where distinct populations regenerated the phenotypic and functional heterogeneity of the parental tumour
- phenotypic conversion among distinct CSC subsets within a tumour

25
Q

What are some models of tumour propagation?

A
  • one CSC subset may be present within the tumour, non CSCs are incapable of generating a tumour
  • multiple distinct CSC pools, each independently capable of tumour propagation, may exit with an individual tumour
  • long-lived dormant CSCs may produce local and/or distant tumour recurrence after activation many years after anti cancer therapy
  • as tumour progression occurs, a second distinct CSC may arise as a result of clonal evolution - this may result from the acquisition of an additional mutation or by epigenetic modification. The more aggressive CSCs will become dominant and drive tumour formation
  • the CSC phenotype may be unstable, resulting in phenotype reversion of cell surface markers and switching of the CSC phenotype - this may occur in response to cell intrinsic or microenvironmental cues
26
Q

What are metastatic CSCs?

A
  • may be the same or distinct from the primary CSC
  • a CSC is responsible for both local and disseminated tumour propagation, a metastatic CSC is only responsible for disseminated
  • genetic/epigenetic mechanisms acting in the primary CSC could lead to the emergence of a self renewing metastatic CSC which expresses distinct markers from the original CSC
  • the metastatic CSC seeds secondary tumours into distant organs through a series of invasive processes
  • in pancreatic cancer, only CD133+CXCR4+ cells show metastatic activity
27
Q

What is the concept of CSC?

A
  1. CSC is a functional definition. They should be defined in functional assays by their ability to generate serially transplantable tumours. Simple marker expression and in vitro assays are not sufficient enough to define CSCs
  2. CSCs may/may not originate from normal stem cells
  3. Metastatic CSCs may be the same or distinct from primary CSCs
  4. CSCs may/may not be rare, and their relative abundance likely varies with individual patient tumours, tumour type, grade and treatment status
  5. Like normal stem cells, CSCs are heterogeneous and their progeny may also posses plasticity, especially accompanying tumour progression
28
Q

Do all cancers harbour CSCs?

A
  • eg melanoma
  • numerous groups have detected sub populations of melanoma cells that fulfil the criteria of CSCs
  • Melanoma may use distinct cellular mechanisms from most other solid malignancies, given the highly migratory nature of neural crest cells
29
Q

How have CSCs and tumour cell plasticity gone through evolution?

A
  • CSC and clonal evolution concepts are not mutually exclusive
  • tumour cell plasticity may contribute to phenotypic and functional heterogeneity
  • many cell surface markers on melanoma cells are reversibly expressed - phenotypically diverse melanoma cells can recapitulate tumour heterogeneity of the parent tumour, irrespective of whether they arose from marker positive cells
30
Q

What are some therapies that target CSCs?

A
  1. Targeting ABC cassette:
    - verapamil
    - MS-209
  2. Targeting surface markers:
    - target CD44/CD90/CD33
  3. Targeting signal cascades:
    - target Notch/Hedgehog/Wnt
  4. Targeting mircoenvironment:
    - CXCL12/CXCR4/VEGF
31
Q

What are some drugs that directly target CSCs

A
  1. WZB117 = pancreatic, ovarian = regulates metabolism
  2. PTC-209 = colorectal = inhibits self renewal
  3. ABT-737 = breast = induces CSC apoptosis
  4. Rituximab = melanoma = inhibits metastasis

Biology of Cancer (19 decks)

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