Lecture 16 - Cancer Stem Cells

What are totipotent zygotes?

• The single cell formed by the union of sperm and egg

• Possesses the unique ability to differentiate into every human cell type

  • This also includes the ability to become placental cells

What are pluripotent embryonic stem cells?

Only appear very early in development and are defined by their two key properties

• Ability to self-renew, diving indefinitely and producing unaltered daughter cells

• Ability to differentiate into specialised cell types, essentially being able to differentiate into any human cell

What is the difference between totipotent and pluripotent cells?

Totipotent and pluripotent cells can both become any human cell.

• HOWEVER, only totipotent cells are capable of becoming extra-embryonic tissue (such as the placenta)

What are multipotent adult stem cells?

• Undifferentiated, tissue-specific cells which are found throughout the body

• Can self-renew and differentiate into a limited set of cell types

  • Restricted to cells within their lineage (e.g. blood, fat, neural, etc)

• Used primarily for repairing damaged tissue

What are oligopotent stem cells?

• Adult stem cells with limited differentiation potential

• More restricted cell types than multipotent stem cells but still more diverse than unipotent stem cells

  • Example: Myeloid/Lymphoid progenitor cells

What are unipotent stem cells?

• Adult stem cells with the lowest differentiation potential

• Are capable of self-renewal and producing only one specific cell type

• Crucial for tissue maintenance, repair and regeneration

• Example: Skin basal cells or muscle stem cells

What governs maximum cell division?

• Length of the telomeres  

  • Hayflick’s limit  

• Once telomeres get too short, cell cannot divide anymore 

What are the two methods of self-renewal?

• Asymmetric division

• Symmetric division

What is asymmetric division?

• E.g. Stem cell attached to basal membrane  

  • When cell divides, one daughter cell retains its attachment to the basal membrane (stem cell)

  • The other daughter cell differentiates, driving tissue renewal

What is symmetric division?

• E.g. Stem cell attached to basal membrane 

  • When cell divides, both daughter cells retrain their attachment to the basal membrane (stem cell)

  • Neither daughter cell differentiates

What was found when Fluorescence-Activated Cell Sorting (FACS) sorted AML cells were injected into SCID mice?

AML could only be transferred to the mice by blasts expressing CD34+ CD38- phenotype

• Only around 1/10000 to 1/1000000 of cells

What are cancer stem cells?

• Potential for extensive proliferation

• Ability to self-renew

• Capacity to cause the heterogenous lineages of cancer cells which comprise the tumour

What was the hypothesis about acute lymphoblastic leukaemia cells when it came to transferring the cancer?

Hypothesis was that only rare immature blasts can transfer the ALL into immune-deficient mice.

What was actually observed when acute lymphoblastic leukaemia was attempted to be transmitted to SCID mice?

Both immature CD34- and mature CD34+ B-cells were capable of transferring the ALL to NOD SCID mice.

What was found when SCID mice and more immunocompromised SCID mice were injected with 4000 melanoma cells?

• In the SCID mice, 1/3 had developed a tumour after 170 days

• In the more compromised SCID mice, 3/3 mice had developed a tumour after only 90 days

What was found when SCID mice and SCID mice + Matrigel were injected with 400 melanoma cells?

• In the SCID mice, 1/3 had developed a tumour after 170 days

• In the SCID mice + Matrigel, 3/3 mice had developed a tumour after only 100 days

What did the mice studies of Melanoma and SCID mice suggest?

• That the stem-cell phenotype some cancer cells expressed is not intrinsic to the cell

  • More mature cancer cells may be capable of re-expressing stem cell markers and becoming cancer stem cells

How is cancer stemness introduced?

• Possible the oncogenic hit occurs in a stem cell, resulting in the production of a cancer stem cell

  • Retains the ability to self-renew

• Also possible the oncogenic hit occurs in a progenitor cell which then reinduce the stem cell phenotype

  • This gives the cell the ability to self-renew

What are the three key models of cancer stem cell production?

• Stochastic model

• Hierarchical model

• Evolution model

What is the Stochastic model of cancer stem cells?

• Stemness is a functional phenotype

  • If a cancer cell is in a bone marrow niche, the signals around it may allow reintroduction of stemness

  • The cell may also have endogenous factors which can reactivate stemness

  • Random

What is the Hierarchical model of cancer stem cells?

• Stemness is within a defined population

• Cancer stem cells self-renew and maintain this defined population

What is the evolution model of cancer stem cells?

• Evolution occurs which creates diversity and potential therapy resistance.

  • This occurs within the other two models

Why is targeting cancer stem cells potentially very useful?

• Maintain and propagate the tumour 

  • Not necessarily the cell in which the tumour originated 

• Retain or evolve to demonstrate stemness 

  • Likely source of relapse  

• Therapies may only kill cancer cells but NOT cancer stem cells

  • The tumour will shrink but has the ability to grow back

What is heterogeneity?

Heterogeneity is diversity across a time point 

What is evolution?

Evolution is diversity over time  

What is Darwinian evolution?

• If treatment is given at a certain time, the heterogeneity of the cells may allow some cells to survive due to some being resistant  

  • Heterogeneity gives the potential to escape treatment

  • Driven by natural selection

What is Parallel evolution?

• E.g. in renal cancer inherited VHL gene mutation puts people at risk 

  • A subsequent SETD2 mutation can trigger cancer  

  • A frameshift mutation, missense mutation and splice site mutation could all occur near simultaneously allowing for many different cancers to develop 

What is Gradualism?

• E.g. a butterfly colour slowly changing over time (gradualism)

  • Such as going from brown to dark grey  

In the case of Burkitt lymphoma, what is a common genetic mutation seen in cancers which have relapsed?

• Many times, in patients who relapse, the cancer has evolved to completely lose their p53 activity  

  • So loss of p53 is not only a marker of poor prognosis early on but is also an indicator of relapse in subsequent cancers  

Why is relapse often an issue when trying to treat cancer?

• Often the relapsed cancer results from a tiny subset of cells within the tumour 

  • May only account for <1% of the tumour  

  • However this small subset is resistant to the therapy, allowing it to survive and then divide again

What is a potential issue with targeting cancer stem cells?

• May be very difficult to target them.

  • Stem cells may be fairly inactive, only producing progenitors every so often  

  • They may also be protected from chemotherapy by the other tumour cells 

• As a result, this has never been accomplished in reality

What are the clinical challenges of targeting cancer stem cells?

• Understanding how the cancer cells maintain the stemness  

• Are there exploitable differences between cancer cells and cancer stem cells 

• How do cancer cells evolve to avoid therapy? Can the mechanism be targeted?