16 stem cells and cellular plasticity Flashcards
What is a stem cell?
An undifferentiated cell capable of indefinite self-renewal and differentiation into other cell types.
What are the two fates of daughter cells after stem cell division?
One maintains stem properties (self-renewal), while the other differentiates into a committed progenitor.
What are the four classes of stem cells?
➡️ Totipotent (zygote) – any cell type.
➡️ Pluripotent (embryonic) – any germ layer.
➡️ Multipotent/Oligopotent – limited cell types.
➡️ Unipotent – one cell type.
Key historical milestones in stem cell research
➡️ 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.
How are cancer stem cells (CSCs) identified?
First identified in human acute myeloid leukaemia by John Dick’s team (1994).
➡️ Defined by their ability to repopulate leukaemia in immunocompromised mice.
What is the classical stochastic model of cancer?
Any cell can become cancerous and propagate the tumour. Cancer develops via clonal selection and Darwinian evolution.
What is the cancer stem cell (CSC) model?
Cancer arises in cells with stem-like properties, forming a hierarchical tumour structure.
What is the Vogelstein model of cancer incidence?
Cancer incidence is proportional to the number of stem cell divisions in a tissue.
Key markers of cancer stem cells (CSCs) in leukaemia?
CD34+CD38−
What CSC markers are found in prostate cancer?
CD44+, a2B1high, CD133+
What CSC markers are found in colon cancer?
CD133+
What is CD133 and why is it important?
A transmembrane glycoprotein that regulates pathways associated with stemness and drug resistance.
What CSC markers are found in multiple myeloma?
CD138+
How can cancer stem cells be isolated?
Colony formation assays, serial transplantation in mice, lineage tracing/ablation.
How is colony formation used to identify CSCs?
CSCs form colonies from single cells, retaining clonogenicity through serial passage.
What are the limitations of in vitro colony formation assays?
Tumour microenvironment, expensive cytokines, need for feeder layers.
How is in vivo transplantation used to identify CSCs?
CSCs form tumours in immunocompromised mice and can be serially transplanted.
What is lineage tracing?
CSC-specific labelling tracks their fate during tumour progression.
What is lineage ablation?
CSCs are selectively eliminated to test their role in tumour maintenance.
Why are CSC-targeted therapies necessary?
Conventional therapies shrink tumours but do not eliminate CSCs, leading to regrowth.
How does CD44 contribute to drug resistance?
CD44 interacts with P-gp, promoting chemoresistance and tumour cell invasion.
What is one method of targeting CD133+ CSCs?
Anti-CD133 antibody linked to nanoparticle-loaded paclitaxel (PT).
How does a bi-specific anti-CD133/CD16 antibody work?
Forms an immune bridge with CD16+ natural killer cells, triggering antibody-dependent cell-mediated cytotoxicity (ADCC).
How can normal stem cells be protected during cancer treatment?
Selective targeting of cancer stem cell markers (e.g., CD133, CD44) while sparing normal stem cells.
What is cancer cell plasticity?
The ability of cancer cells to change phenotype without genetic mutation.
How does cancer cell plasticity contribute to drug resistance?
Allows cells to evade therapy, modify the microenvironment, and resist immune attacks.
What is epithelial-mesenchymal transition (EMT)?
A process where epithelial cells lose polarity and gain a mesenchymal, migratory phenotype.
How does EMT contribute to cancer progression?
EMT correlates with high tumour grade, invasion, and metastasis.
What molecular changes drive EMT?
E-cadherin downregulation, Zinc (Zn2+)-induced migration and invasion.
What is the reverse process of EMT?
Mesenchymal-to-epithelial transition (MET).
How do pre-existing mutations drive therapy resistance?
Mutant tumour cells survive therapy and proliferate, leading to relapse.
How do therapy-induced mutations drive resistance?
Treatment causes new mutations, leading to the emergence of resistant clones.
How is EMT linked to therapy resistance?
Mesenchymal cancer cells are more chemoresistant and resist immune attacks.
What role does the tumour microenvironment play in resistance?
Becomes immune-suppressive, reducing cytotoxic T-cell efficacy.
How does cancer cell dormancy contribute to resistance?
Some cancer cells enter a drug-tolerant dormant state and reactivate after therapy.
Can cancer cells be reprogrammed to reduce malignancy?
Yes, transcriptional reprogramming can alter their state to increase susceptibility to treatment.
Example of plasticity-based therapy: Acute promyelocytic leukaemia
Treatment with retinoic acid overcomes transcriptional repression of RARA genes, restoring differentiation.
Why is tumour heterogeneity a challenge for treatment?
Cancer evolves through mutation and plasticity, making it highly adaptable.
What are the five stages of tumour evolution?
Initiation → Progression → Presentation → Remission → Relapse.
What is the key difference between multipotent and oligopotent stem cells?
Multipotent cells can differentiate into multiple cell types, while oligopotent cells can only differentiate into a few closely related types.
What are the limitations of stem cell therapies?
Ethical concerns, immune rejection, tumorigenic potential, difficulty in differentiation control.
What are the challenges in identifying cancer stem cells (CSCs)?
Heterogeneity in marker expression, variations across cancer types, influence of tumour microenvironment.
What is the role of self-renewal in CSCs?
CSCs self-renew through asymmetric division, allowing tumour maintenance and resistance.
How do CSCs contribute to metastasis?
CSCs survive in circulation, adapt to new environments, and initiate secondary tumours at distant sites.
What is the hierarchy of leukaemia stem cells (LSCs)?
HSC (SRC) → LSC (SL-IC) → Leukemic LTC-IC → Leukemic CFU → Leukemic blast cells → unregulated proliferation.
What is the role of haematopoietic stem cells (HSCs) in leukaemia?
HSCs may acquire mutations that lead to the transformation into leukaemic stem cells (LSCs).
What is the function of ABCG2 in CSCs?
ABCG2 is an efflux transporter that contributes to drug resistance by expelling chemotherapy drugs.
What is ALDH and why is it significant in CSCs?
ALDH is an enzyme that detoxifies reactive oxygen species and is associated with chemoresistance and stem-like properties.
What is the significance of CD90 in gliomas and liver cancer?
CD90 is a marker of CSCs that promotes tumour progression and invasiveness.
Why is serial transplantation a gold standard for CSC identification?
It demonstrates self-renewal by showing that a small CSC population can generate new tumours across multiple generations of mice.
What is a limitation of lineage tracing in CSC studies?
Tracking is complex in heterogeneous tumours, and marker expression may change over time.
What are the key transcription factors driving EMT?
SNAIL, TWIST, ZEB1/ZEB2 – repress E-cadherin, promote invasion and metastasis.
How does EMT influence immune evasion?
EMT reduces tumour antigen expression, making cancer cells less visible to immune cells.
What is the MET process in metastasis?
Mesenchymal cells revert back to epithelial cells (MET) to colonise distant organs.
How does the tumour microenvironment contribute to resistance?
Hypoxia, inflammatory signals, and stromal interactions enhance CSC survival.
What is drug-tolerant persister (DTP) cell state?
A reversible, low-proliferation state that allows CSCs to survive therapy and reinitiate growth.
What is one strategy for targeting plasticity in therapy-resistant cancers?
Differentiation therapy, forcing CSCs to become mature, non-dividing cells.
What is an example of differentiation therapy?
Acute promyelocytic leukaemia (APL) treated with all-trans retinoic acid (ATRA) to induce differentiation.
What is one approach to reprogramming cancer cells for treatment?
Epigenetic drugs can alter gene expression and force tumour cells into a more treatable state.
