Cancer Stem Cells

Question 1

What is a stem cell?

Answer 1

A stem cell is an undifferentiated / unspecified cell that has the ability to self-renew or mature and differentiate.
Immortal

Question 2

What is a committed progenitor cell?

Answer 2

A transiently amplifying cell that is destined to differentiate.

Question 3

How do stem cells drive adult intestinal homeostasis and regeneration.

Answer 3

GSCs
Differentiate and move up the crypt walls. Wnt overexpression causes cancer.
Wnt (colon), Shh (blastoma) and Notch (leukaemia) pathways are deregulated in cancer cells.

Question 4

What are the two types of tumour heterogeneity?

Answer 4

Intratumoral heterogeneity – expression of different markers among cancer cells.
Intertumoral heterogeneity – differences in tumours from different patients with a given cancer.

Question 5

What are the 3 mechanisms of tumour heterogeneity?

Answer 5

1. Clonal evolution of genomic landscape in individual tumours.
   influenced by: exposure (lifestyle) SELECTIVE PRESSURES - genetics, system regulators (hormones), local regulators (nutrients, space), and architectural constraints (membranes)
   Evolve via a Darwinian process, somatic mutations confer selective advantages to more fit clones.
2. The existence of populations of cancer stem cells (CSCs).
   Stem cells are long-lived, they acquire a lot of different sequential mutations to convert a normal cell into a malignant one. Only a small subset of tumour cells are CSCs and capable of propagating the cancer.
3. Tumour microenvironment

Question 6

HSCs

Answer 6

Long term stem cells with CD34+ and CD38- convert to multipotent progenitor cells, as well as self-renewing.
LT - ST(CD34+) - MPP (CD34+, FLK2+) - LRP
LRP = Tcells, Bcells, WBC, RBC, NK cells

Question 7

LSCs

Answer 7

Leukemic
Exist in human acute myeloid leukaemia (AML)
Not all leukemic cells are able to propagate leukaemia when transplanted into immunodeficient mice.
CD38- causes blocked differentiation and leukaemia. CD38+/CD34+ LSCs show no disease.

Question 8

BCSCs

Answer 8

If breast cancer cells are CD44+/CD24-, there is a lower chance of survival and greater metastases in the stem cell phenotype.

Question 9

2 model of tumour growth and heterogeneity.

Answer 9

1. STOCHASTIC - The conventional model - All cells are potential cancer cells but have a low probability of proliferation. Cells are equally tumourigenic.
   Genetically divergent clonal subpopulations exist within the most aggressive tumours and drive their progression.
2. HIERARCHICAL - The stem cell model - Only a small definable subset of cancer cells are CSCs that have the ability to proliferate indefinitely.

Question 10

Intrinsic regulation of cancer cells.

Answer 10

Caused by EMT. EMT occurs through distinct intermediate states (hybrid EMT state - a partial EMT where individual cells express epithelial and mesenchymal markers and when they have their highest plasticity)
Research - Genetic fate mapping of propagating CSCs in vivo showed the first evidence of subpopulations and different EMT stages.
Hybrid state = most metastatic, different niches regulate transition states, lead to heterogeneity.

Question 11

Extrinsic regulation of cancer cells.

Answer 11

Extrinsic regulation of CSCs is by their niche, through cell-cell interactions, secreted factors, cell-matrix interactions and biophysical niche properties.

• Endothelial cells (perivascular niche, EMT)
• Hypoxia (rapid proliferation leads to hypoxic environment, HIFs cause EMT)
• Inflammation (TAMs form a metastatic niche to cause EMT)
• Fibroblasts (synthesise the ECM to support cancer cell function)

Question 12

How do CSCs promote metastasis?

Answer 12

Only a subset of long-term self-renewing CSCs can drive metastasis.
EMT promotes metastatic dissemination and acquisition of CSC properties - characterised by dormancy and can occur years after successful first treatment.
Metastatic cells can undergo MET to colonise new distant organs.
Seeding - Survival - Dormancy - Colonisation - Growth

Question 13

THERAPEUTIC IMPLICATIONS OF CANCER STEM CELLS

Answer 13

Resistance Mechanisms:

• Resistant to CSC therapy - tumour microenvironment, DNA repair activation, DNA damage resistance.
• Acquisition of CSC properties - stem cell reprogramming and EMT. Both lead to relapse.

Conventional targeted therapies are based on targeting non-tumourigenic cells. Saves time, kills almost all rapidly dividing cells but relapse will occur.
Novel targeted therapies kills cancer stem cells so the tumour will degenerate and cannot be propagated. No relapse.
Combination therapy

Question 14

What is stemness?

Answer 14

During EMT, epithelial cells become plastic in the stemness window and gain characteristics that make they different from normal cells and become mesenchymal.

Question 15

3 future directions of stem cell therapies

Answer 15

• ID novel cell markers of sub-populations.
• Evaluate CSCs numbers of progeny at different tumour stages.
• Better evaluate how CSCs compete / collaborate during tumour growth.