16 stem cells and cellular plasticity

Question 1

What is a stem cell?

Answer 1

An undifferentiated cell capable of indefinite self-renewal and differentiation into other cell types.

Question 2

What are the two fates of daughter cells after stem cell division?

Answer 2

One maintains stem properties (self-renewal), while the other differentiates into a committed progenitor.

Question 3

What are the four classes of stem cells?

Answer 3

➡️ Totipotent (zygote) – any cell type.
➡️ Pluripotent (embryonic) – any germ layer.
➡️ Multipotent/Oligopotent – limited cell types.
➡️ Unipotent – one cell type.

Question 4

Key historical milestones in stem cell research

Answer 4

➡️ 1968: First bone marrow transplant.
➡️ 1978: Cord blood stem cells discovered.
➡️ 1981: First mouse embryonic stem cell line.
➡️ 1995: First human embryonic stem cell line.
➡️ 1996: Dolly the sheep cloned.

Question 5

How are cancer stem cells (CSCs) identified?

Answer 5

First identified in human acute myeloid leukaemia by John Dick’s team (1994).
➡️ Defined by their ability to repopulate leukaemia in immunocompromised mice.

Question 6

What is the classical stochastic model of cancer?

Answer 6

Any cell can become cancerous and propagate the tumour. Cancer develops via clonal selection and Darwinian evolution.

Question 7

What is the cancer stem cell (CSC) model?

Answer 7

Cancer arises in cells with stem-like properties, forming a hierarchical tumour structure.

Question 8

What is the Vogelstein model of cancer incidence?

Answer 8

Cancer incidence is proportional to the number of stem cell divisions in a tissue.

Question 9

Key markers of cancer stem cells (CSCs) in leukaemia?

Answer 9

CD34+CD38−

Question 10

What CSC markers are found in prostate cancer?

Answer 10

CD44+, a2B1high, CD133+

Question 11

What CSC markers are found in colon cancer?

Answer 11

CD133+

Question 12

What is CD133 and why is it important?

Answer 12

A transmembrane glycoprotein that regulates pathways associated with stemness and drug resistance.

Question 13

What CSC markers are found in multiple myeloma?

Answer 13

CD138+

Question 14

How can cancer stem cells be isolated?

Answer 14

Colony formation assays, serial transplantation in mice, lineage tracing/ablation.

Question 15

How is colony formation used to identify CSCs?

Answer 15

CSCs form colonies from single cells, retaining clonogenicity through serial passage.

Question 16

What are the limitations of in vitro colony formation assays?

Answer 16

Tumour microenvironment, expensive cytokines, need for feeder layers.

Question 17

How is in vivo transplantation used to identify CSCs?

Answer 17

CSCs form tumours in immunocompromised mice and can be serially transplanted.

Question 18

What is lineage tracing?

Answer 18

CSC-specific labelling tracks their fate during tumour progression.

Question 19

What is lineage ablation?

Answer 19

CSCs are selectively eliminated to test their role in tumour maintenance.

Question 20

Why are CSC-targeted therapies necessary?

Answer 20

Conventional therapies shrink tumours but do not eliminate CSCs, leading to regrowth.

Question 21

How does CD44 contribute to drug resistance?

Answer 21

CD44 interacts with P-gp, promoting chemoresistance and tumour cell invasion.

Question 22

What is one method of targeting CD133+ CSCs?

Answer 22

Anti-CD133 antibody linked to nanoparticle-loaded paclitaxel (PT).

Question 23

How does a bi-specific anti-CD133/CD16 antibody work?

Answer 23

Forms an immune bridge with CD16+ natural killer cells, triggering antibody-dependent cell-mediated cytotoxicity (ADCC).

Question 24

How can normal stem cells be protected during cancer treatment?

Answer 24

Selective targeting of cancer stem cell markers (e.g., CD133, CD44) while sparing normal stem cells.

Question 25

What is cancer cell plasticity?

Answer 25

The ability of cancer cells to change phenotype without genetic mutation.

Question 26

How does cancer cell plasticity contribute to drug resistance?

Answer 26

Allows cells to evade therapy, modify the microenvironment, and resist immune attacks.

Question 27

What is epithelial-mesenchymal transition (EMT)?

Answer 27

A process where epithelial cells lose polarity and gain a mesenchymal, migratory phenotype.

Question 28

How does EMT contribute to cancer progression?

Answer 28

EMT correlates with high tumour grade, invasion, and metastasis.

Question 29

What molecular changes drive EMT?

Answer 29

E-cadherin downregulation, Zinc (Zn2+)-induced migration and invasion.

Question 30

What is the reverse process of EMT?

Answer 30

Mesenchymal-to-epithelial transition (MET).

Question 31

How do pre-existing mutations drive therapy resistance?

Answer 31

Mutant tumour cells survive therapy and proliferate, leading to relapse.

Question 32

How do therapy-induced mutations drive resistance?

Answer 32

Treatment causes new mutations, leading to the emergence of resistant clones.

Question 33

How is EMT linked to therapy resistance?

Answer 33

Mesenchymal cancer cells are more chemoresistant and resist immune attacks.

Question 34

What role does the tumour microenvironment play in resistance?

Answer 34

Becomes immune-suppressive, reducing cytotoxic T-cell efficacy.

Question 35

How does cancer cell dormancy contribute to resistance?

Answer 35

Some cancer cells enter a drug-tolerant dormant state and reactivate after therapy.

Question 36

Can cancer cells be reprogrammed to reduce malignancy?

Answer 36

Yes, transcriptional reprogramming can alter their state to increase susceptibility to treatment.

Question 37

Example of plasticity-based therapy: Acute promyelocytic leukaemia

Answer 37

Treatment with retinoic acid overcomes transcriptional repression of RARA genes, restoring differentiation.

Question 38

Why is tumour heterogeneity a challenge for treatment?

Answer 38

Cancer evolves through mutation and plasticity, making it highly adaptable.

Question 39

What are the five stages of tumour evolution?

Answer 39

Initiation → Progression → Presentation → Remission → Relapse.

Question 40

What is the key difference between multipotent and oligopotent stem cells?

Answer 40

Multipotent cells can differentiate into multiple cell types, while oligopotent cells can only differentiate into a few closely related types.

Question 41

What are the limitations of stem cell therapies?

Answer 41

Ethical concerns, immune rejection, tumorigenic potential, difficulty in differentiation control.

Question 42

What are the challenges in identifying cancer stem cells (CSCs)?

Answer 42

Heterogeneity in marker expression, variations across cancer types, influence of tumour microenvironment.

Question 43

What is the role of self-renewal in CSCs?

Answer 43

CSCs self-renew through asymmetric division, allowing tumour maintenance and resistance.

Question 44

How do CSCs contribute to metastasis?

Answer 44

CSCs survive in circulation, adapt to new environments, and initiate secondary tumours at distant sites.

Question 45

What is the hierarchy of leukaemia stem cells (LSCs)?

Answer 45

HSC (SRC) → LSC (SL-IC) → Leukemic LTC-IC → Leukemic CFU → Leukemic blast cells → unregulated proliferation.

Question 46

What is the role of haematopoietic stem cells (HSCs) in leukaemia?

Answer 46

HSCs may acquire mutations that lead to the transformation into leukaemic stem cells (LSCs).

Question 47

What is the function of ABCG2 in CSCs?

Answer 47

ABCG2 is an efflux transporter that contributes to drug resistance by expelling chemotherapy drugs.

Question 48

What is ALDH and why is it significant in CSCs?

Answer 48

ALDH is an enzyme that detoxifies reactive oxygen species and is associated with chemoresistance and stem-like properties.

Question 49

What is the significance of CD90 in gliomas and liver cancer?

Answer 49

CD90 is a marker of CSCs that promotes tumour progression and invasiveness.

Question 50

Why is serial transplantation a gold standard for CSC identification?

Answer 50

It demonstrates self-renewal by showing that a small CSC population can generate new tumours across multiple generations of mice.

Question 51

What is a limitation of lineage tracing in CSC studies?

Answer 51

Tracking is complex in heterogeneous tumours, and marker expression may change over time.

Question 52

What are the key transcription factors driving EMT?

Answer 52

SNAIL, TWIST, ZEB1/ZEB2 – repress E-cadherin, promote invasion and metastasis.

Question 53

How does EMT influence immune evasion?

Answer 53

EMT reduces tumour antigen expression, making cancer cells less visible to immune cells.

Question 54

What is the MET process in metastasis?

Answer 54

Mesenchymal cells revert back to epithelial cells (MET) to colonise distant organs.

Question 55

How does the tumour microenvironment contribute to resistance?

Answer 55

Hypoxia, inflammatory signals, and stromal interactions enhance CSC survival.

Question 56

What is drug-tolerant persister (DTP) cell state?

Answer 56

A reversible, low-proliferation state that allows CSCs to survive therapy and reinitiate growth.

Question 57

What is one strategy for targeting plasticity in therapy-resistant cancers?

Answer 57

Differentiation therapy, forcing CSCs to become mature, non-dividing cells.

Question 58

What is an example of differentiation therapy?

Answer 58

Acute promyelocytic leukaemia (APL) treated with all-trans retinoic acid (ATRA) to induce differentiation.

Question 59

What is one approach to reprogramming cancer cells for treatment?

Answer 59

Epigenetic drugs can alter gene expression and force tumour cells into a more treatable state.