Lecture 7 - Cancer Stem Cells 2 Flashcards
What are the two critical features of cancer progression and prognosis?
The ability of the tumour to grow and spread to secondary sites
These features are essential for understanding cancer development.
Define angiogenesis in the context of cancer.
Growth of new blood vessels to provide the tumour with oxygen and nutrients
Angiogenesis is crucial for tumour survival and growth.
E.g. endothelial cells migrating
What is metastasis?
Ability of tumour cells to break away from primary tumour, travel through the body and recolonise at a distant site
Metastasis is a key factor in cancer severity.
What common feature do angiogenesis and metastasis share?
Both involve mobility/migration of cells
This mobility is crucial for cancer spread.
Most normal cells once formed are fairly static in regards to movement.
What is Epithelial-Mesenchymal Transition (EMT)?
A process where epithelial cells gain migratory capabilities and can contribute to metastasis
EMT is also a well-known feature during embryogenesis.
What initiates the mechanism of EMT?
Signals from tumour stroma/microenvironment
These signals include HGF and TGF-b.
From niches around the stem cells.
What does TGF-b activate in the context of EMT?
Smad complex
This activation is crucial for the EMT process.
List some transcription factors activated during EMT.
- Twist
- Snail
- Slug
- ZEB-1
These factors help repress epithelial genes.
Controls EMT, so upregulated in metastatic cancer.
Activated by TBF-b?
What is the role of PcG in EMT?
Repress epithelial genes by epigenetic mechanisms
This repression is essential for the transition to a migratory phenotype.
Reversal of E- and N-cadherin driven by epigenetics.
What constitutes the tumour microenvironment?
TME is dynamic and complex environment. Collection of cancer cells and various other cell types, including immune cells, stromal cells, endotherlial cells, and the extracellular matrix and blood vessels.
This includes various components that support tumour survival.
Tumour microenvironment as important as the cancer cells themselves, e.g. growth, metastasis, etc…
What is a hallmark of cancer regarding immune response?
Avoidance of immune destruction
This characteristic allows cancer cells to evade the immune system.
Name some mechanisms of tumour-mediated immune evasion.
- Loss of tumour antigens
- Downregulation of MHC
- Overexpression of immune checkpoint proteins (PD-L1)
- Overexpression of anti-apoptotic molecules
- Secretion of immunosuppressive molecules (TGF-b, IL-10, VEGF)
- Switching of macrophages to M2 phenotype
These mechanisms collectively help in the evasion of immune detection.
Pro-inflammatory M1 phenotype to M2 more supportive phenotype.
Fill in the blank: The link between characteristics and processes in cancer is _______.
Mesenchymal Stem cells
Mesenchymal stem cells play a significant role in the tumor microenvironment.
The factors secreted and processes supported are similar.
What must therapies target in addition to the non-stem cells in tumors?
Therapies need to target the small population of tumour-initiating cancer cells
This is crucial for effective cancer treatment.
Therapies targeting rapidly proliferating, non-differentiated cells.
However, therapies must not affect normal stem cells as these are needed for repair and normal function.
What are ABC transporters and their role in stem cells?
APC transporters are membrane proteins that are responsible for ATP-powered translocation of substrates.
Presence of ABC transporters (P-glycoprotein) protects stem cells against foreign toxins
Expression is lost on differentiation.
Overexpression of ABC transporters to rapidly pump out toxins as a safety mechanism.
What issue arises with ABC transporters in tumor cells?
In tumor cells, this manifests as drug resistance
This has led to the development of ABC inhibitors as adjuvant therapy - could target WT stem cells though.
What initial compounds were toxic in the development of ABC inhibitors?
Verapamil, cyclosporin A
These were early compounds used but were found to be toxic.
Progress has been made with natutral products such as flavonoids and terponoids.
What is the significance of the Wnt pathway in cancer therapy?
Interest in β-catenin/TCF inhibition and targeting downstream of APC/Axin
Wnt is reuired to target downstream of APC/Axin.
Inhibition of TCF induces differentiation of colorectal cancer cells.
What causes resistance to chemotherapy and radiation in cancer cells?
Bmi-1 expression causes resistance due to DNA repair
Enhanced EMT occurs due to hypoxia-induction of HIF-1α/Bmi complexes.
What is the effect of inhibiting Bmi-1 in cancer treatment?
Inhibition of Bmi-1 sensitizes cancer stem cells to chemotherapy and radiotherapy, activates immune responses, sensitises CSCs to anti-PD-1 therapies by recruitment of CD8+ cells.
It also activates immune responses.
What is PTC-596 and its role in cancer treatment?
An orally active and selective Bmi-1 inhibitor inducing p53-independent mitochondrial apoptosis in AML progenitor cells
Also being tested in myelomas and gliomas.
What was the outcome of adding arsenic trioxide in APL treatment?
Reversed resistance and eradicated tumor cells
ATRA converts PML-RAR complex from repressor to transactivator - drives expression of differentiation genes (e.g. C/EBP). Subsequently degrades TF complex)
What are MMP inhibitors and their challenges?
MMP inhibitors block activity of matrix metalloproteinases (MMPs) whcih are enzymes responsible for degrading the ECM)
MMP inhibitors (e.g., Marimastat) face lack of efficacy and toxicity due to lack of specificity
Ongoing studies aim to develop antibodies to membrane-bound MMPs.
What is the role of pharmacological targeting of netrin-1 in cancer?
Inhibits EMT in cancer
This presents opportunities for pharmacological intervention.
